Sustainable Release Selenium Laden with SiO2 Restoring Peripheral Nerve Injury via Modulating PI3K/AKT Pathway Signaling Pathway.

Background: Inhibiting ROS overproduction is considered a very effective strategy for the treatment of peripheral nerve injuries, and Se has a remarkable antioxidant effect; however, since the difference between the effective concentration of Se and the toxic dose is not large, we synthesized a nanomaterial that can release Se slowly so that it can be used more effectively. Methods: Se@SiO2 NPs were synthesized using a mixture of Cu2-x Se nanocrystals, and the mechanism of action of Se@SiO2 NPs was initially explored by performing sequencing, immunofluorescence staining and Western blotting of cellular experiments. The mechanism of action of Se@SiO2 NPs was further determined by performing behavioral assays after animal experiments and by sampling the material for histological staining, immunofluorescence staining, and ELISA. The effects, mechanisms and biocompatibility of Se@SiO2 NPs for peripheral nerve regeneration were determined. Results: Porous Se@SiO2 was successfully synthesized, had good particle properties, and could release Se slowly. CCK-8 experiments revealed that the optimal experimental doses were 100 µM H2O2 and 200 µg/mL Se@SiO2, and RNA-seq revealed that porous Se@SiO2 was associated with cell proliferation, apoptosis, and the PI3K/AKT pathway. WB showed that porous Se@SiO2 could increase the expression of cell proliferation antigens (PCNA and S100) and antiapoptotic proteins (Bcl-2), decrease the expression of proapoptotic proteins (Bax), and increase the expression of antioxidative stress proteins (Nrf2, HO-1, and SOD2). EdU cell proliferation and ROS fluorescence assays showed that porous Se@SiO2 promoted cell proliferation and reduced ROS levels. The therapeutic effect of LY294002 (a PI3K/AKT pathway inhibitor) was decreased significantly and its effect was lost when it was added simultaneously with porous Se@SiO2. Animal experiments revealed that the regenerated nerve fiber density, myelin thickness, axon area, gastrocnemius muscle wet-to-weight ratio, myofiber area, sciatic nerve function index (SFI), CMAP, apoptotic cell ratio, and levels of antioxidative stress proteins and anti-inflammatory factors were increased following the administration of porous Se@SiO2. The levels of oxidative stress proteins and anti-inflammatory factors were significantly greater in the Se@SiO2 group than in the PNI group, and the effect of LY294002 was decreased significantly and was lost when it was added simultaneously with porous Se@SiO2. Conclusion: Se@SiO2 NPs are promising, economical and effective Se-releasing nanomaterials that can effectively reduce ROS production, inhibit apoptosis and promote cell proliferation after nerve injury via the PI3K/AKT pathway, ultimately accelerating nerve regeneration. These findings could be used to design new, promising drugs for the treatment of peripheral nerve injury.

A tacrolimus-eluting nerve guidance conduit enhances regeneration in a critical-sized peripheral nerve injury rat model.

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered.

PLCL/SF/NGF nerve conduit loaded with RGD-TA-PPY hydrogel promotes regeneration of sciatic nerve defects in rats through PI3K/AKT signalling pathways.

Peripheral nerve defect are common clinical problem caused by trauma or other diseases, often leading to the loss of sensory and motor function in patients. Autologous nerve transplantation has been the gold standard for repairing peripheral nerve defects, but its clinical application is limited due to insufficient donor tissue. In recent years, the application of tissue engineering methods to synthesize nerve conduits for treating peripheral nerve defect has become a current research focus. This study introduces a novel approach for treating peripheral nerve defects using a tissue-engineered PLCL/SF/NGF@TA-PPy-RGD conduit. The conduit was fabricated by combining electrospun PLCL/SF with an NGF-loaded conductive TA-PPy-RGD gel. The gel, synthesized from RGD-modified tannic acid (TA) and polypyrrole (PPy), provides growth anchor points for nerve cells. In vitro results showed that this hybrid conduit could enhance PC12 cell proliferation, migration, and reduce apoptosis under oxidative stress. Furthermore, the conduit activated the PI3K/AKT signalling pathway in PC12 cells. In a rat model of sciatic nerve defect, the PLCL/SF/NGF@TA-PPy-RGD conduit significantly improved motor function, gastrocnemius muscle function, and myelin sheath axon thickness, comparable to autologous nerve transplantation. It also promoted angiogenesis around the nerve defect. This study suggests that PLCL/SF/NGF@TA-PPy-RGD conduits provide a conducive environment for nerve regeneration, offering a new strategy for peripheral nerve defect treatment, this study provided theoretical basis and new strategies for the research and treatment of peripheral nerve defect.

Iatrogenic Sciatic Nerve Injury in Posterior Acetabular Surgery: Surgeon More Predictive Than Position.

OBJECTIVES: To identify factors that contribute to iatrogenic sciatic nerve palsy during acetabular surgery through a Kocher-Langenbeck approach and to evaluate if variation among individual surgeons exists. DESIGN: Retrospective cohort. SETTING: Level I trauma center. PATIENT SELECTION CRITERIA: Adults undergoing fixation of acetabular fractures (AO/OTA 62) through a posterior approach by 9 orthopaedic traumatologists between November 2010 and November 2022. OUTCOME MEASURES AND COMPARISONS: The prevalence of iatrogenic sciatic nerve palsy and comparison of the prevalence and risk of palsy between prone and lateral positions before and after adjusting for individual surgeon and the presence of transverse fracture patterns in logistic regression. Comparison of the prevalence of palsy between high-volume (>1 patient/month) and low-volume surgeons. RESULTS: A total of 644 acetabular fractures repaired through a posterior approach were included (median age 39 years, 72% male). Twenty of 644 surgeries (3.1%) resulted in iatrogenic sciatic nerve palsy with no significant difference between the prone (3.1%, 95% confidence interval [CI], 1.9%-4.9%) and lateral (3.3%, 95% CI, 1.3%-8.1%) positions (P = 0.64). Logistic regression adjusting for surgeon and transverse fracture pattern demonstrated no significant effect for positions (odds ratio 1.0, 95% CI, 0.3-3.9). Transverse fracture pattern was associated with increased palsy risk (odds ratio 3.0, 95% CI, 1.1-7.9). Individual surgeon was significantly associated with iatrogenic palsy (P < 0.02). CONCLUSIONS: Surgeon and the presence of a transverse fracture line predicted iatrogenic nerve palsy after a posterior approach to the acetabulum in this single-center cohort. Surgeons should perform the Kocher-Langenbeck approach for acetabular fixation in the position they deem most appropriate, as the position was not associated with the rate of iatrogenic palsy in this series. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Repetitive magnetic stimulation prevents dorsal root ganglion neuron death and enhances nerve regeneration in a sciatic nerve injury rat model.

Peripheral nerve injury (PNI) often leads to retrograde cell death in the spinal cord and dorsal root ganglia (DRG), hindering nerve regeneration and functional recovery. Repetitive magnetic stimulation (rMS) promotes nerve regeneration following PNI. Therefore, this study aimed to investigate the effects of rMS on post-injury neuronal death and nerve regeneration. Seventy-two rats underwent autologous sciatic nerve grafting and were divided into two groups: the rMS group, which received rMS and the control (CON) group, which received no treatment. Motor neuron, DRG neuron, and caspase-3 positive DRG neuron counts, as well as DRG mRNA expression analyses, were conducted at 1-, 4-, and 8-weeks post-injury. Functional and axon regeneration analyses were performed at 8-weeks post-injury. The CON group demonstrated a decreased DRG neuron count starting from 1 week post-injury, whereas the rMS group exhibited significantly higher DRG neuron counts at 1- and 4-weeks post-injury. At 8-weeks post-injury, the rMS group demonstrated a significantly greater myelinated nerve fiber density in autografted nerves. Furthermore, functional analysis showed significant improvements in latency and toe angle in the rMS group. Overall, these results suggest that rMS can prevent DRG neuron death and enhance nerve regeneration and motor function recovery after PNI.

Multilevel neurium-mimetic individualized graft via additive manufacturing for efficient tissue repair.

Complicated peripheral nerve injuries or defects, especially at branching sites, remain a prominent clinical challenge after the application of different treatment strategies. Current nerve grafts fail to match the expected shape and size for delicate and precise branched nerve repair on a case-by-case basis, and there is a lack of geometrical and microscale regenerative navigation. In this study, we develop a sugar painting-inspired individualized multilevel epi-/peri-/endoneurium-mimetic device (SpinMed) to customize natural cues, featuring a selectively protective outer sheath and an instructive core, to support rapid vascular reconstruction and consequent efficient neurite extension along the defect area. The biomimetic perineurium dictates host-guest crosslinking in which new vessels secrete multimerin 1 binding to the fibroin filler surface as an anchor, contributing to the biological endoneurium that promotes Schwann cell homing and remyelination. SpinMed implantation into rat sciatic nerve defects yields a satisfactory outcome in terms of structural reconstruction, with sensory and locomotive function restoration. We further customize SpinMed grafts based on anatomy and digital imaging, achieving rapid repair of the nerve trunk and branches superior to that achieved by autografts and decellularized grafts in a specific beagle nerve defect model, with reliable biosafety. Overall, this intelligent art-inspired biomimetic design offers a facile way to customize sophisticated high-performance nerve grafts and holds great potential for application in translational regenerative medicine.

Exosomes repairment for sciatic nerve injury: a cell-free therapy.

Sciatic nerve injury (SNI) is a common type of peripheral nerve injury typically resulting from trauma, such as contusion, sharp force injuries, drug injections, pelvic fractures, or hip dislocations. It leads to both sensory and motor dysfunctions, characterized by pain, numbness, loss of sensation, muscle atrophy, reduced muscle tone, and limb paralysis. These symptoms can significantly diminish a patient's quality of life. Following SNI, Wallerian degeneration occurs, which activates various signaling pathways, inflammatory factors, and epigenetic regulators. Despite the availability of several surgical and nonsurgical treatments, their effectiveness remains suboptimal. Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm, originating from the endoplasmic reticulum. They play a crucial role in facilitating intercellular communication and have emerged as highly promising vehicles for drug delivery. Increasing evidence supports the significant potential of exosomes in repairing SNI. This review delves into the pathological progression of SNI, techniques for generating exosomes, the molecular mechanisms behind SNI recovery with exosomes, the effectiveness of combining exosomes with other approaches for SNI repair, and the changes and future outlook for utilizing exosomes in SNI recovery.

Efficacy of using adipose-derived stem cells and PRP on regeneration of 40 -mm long sciatic nerve defect bridged by polyglycolic-polypropylene mesh in canine model.

BACKGROUND: Sciatic nerve repair becomes a focus of research in neurological aspect to restore the normal physical ability of the animal to stand and walk. Tissue engineered nerve grafts (TENGs) provide a promising alternative therapy for regeneration of large gap defects. The present study investigates the regenerative capacity of PRP, ADSCs, and PRP mixed ADSCs on a long sciatic nerve defect (40-mm) bridged by a polyglycolic polypropylene (PGA-PRL) mesh which acts as a neural scaffold. MATERIALS AND METHODS: The study was conducted on 12 adult male mongrel dogs that were randomly divided into 4 groups: Group I (scaffold group); where the sciatic defect was bridged by a (PGA-PRL) mesh only while the mesh was injected with ADSCs in Group II (ADSCs group), PRP in Group III (PRP group). Mixture of PRP and ADSCs was allocated in Group IV (PRP + ADSCs group). Monthly, all animals were monitored for improvement in their gait and a numerical lameness score was recorded for all groups. 6 months-post surgery, the structural and functional recovery of sciatic nerve was evaluated electrophysiologically, and on the level of gene expression, and both sciatic nerve and the gastrocnemius muscle were evaluated morphometrically, histopathologically. RESULTS: Numerical lameness score showed improvement in the motor activities of both Group II and Group III followed by Group IV and the scaffold group showed mild improvement even after 6 months. Histopathologically, all treated groups showed axonal sprouting and numerous regenerated fascicles with obvious angiogenesis in proximal cut, and distal portion where Group IV exhibited a significant remyelination with the MCOOL technique. The regenerative ratio of gastrocnemius muscle was 23.81%, 56.68%, 52.06% and 40.69% for Group I, II, III and IV; respectively. The expression of NGF showed significant up regulation in the proximal portion for both Group III and Group IV (P ≤ 0.0001) while Group II showed no significant difference. PDGF-A, and VEGF expressions were up-regulated in Group II, III, and IV whereas Group I showed significant down-regulation for NGF, PDGF-A, and VEGF (P ≤ 0.0001). CONCLUSION: ADSCs have a great role in restoring the damaged nerve fibers by secreting several types of growth factors like NGF that have a proliferative effect on Schwann cells and their migration. In addition, PRP therapy potentiates the effect of ADSCs by synthesis another growth factors such as PDGF-A, VEGF, NGF for better healing of large sciatic gap defects.

Biological characteristics of tissue engineered-nerve grafts enhancing peripheral nerve regeneration.

BACKGROUND: A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). METHODS: In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein-protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. RESULTS: The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1ß and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-ß, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. CONCLUSIONS: This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

Efficacy of 3D printed anatomically equivalent thermoplastic polyurethane guide conduits in promoting the regeneration of critical-sized peripheral nerve defects.

Three-dimensional (3D) printing is an emerging tool for creating patient-specific tissue constructs analogous to the native tissue microarchitecture. In this study, anatomically equivalent 3D nerve conduits were developed using thermoplastic polyurethane (TPU) by combining reverse engineering and material extrusion (i.e. fused deposition modeling) technique. Printing parameters were optimized to fabricate nerve-equivalent TPU constructs. The TPU constructs printed with different infill densities supported the adhesion, proliferation, and gene expression of neuronal cells. Subcutaneous implantation of the TPU constructs for three months in rats showed neovascularization with negligible local tissue inflammatory reactions and was classified as a non-irritant biomaterial as per ISO 10993-6. To performin vivoefficacy studies, nerve conduits equivalent to rat's sciatic nerve were fabricated and bridged in a 10 mm sciatic nerve transection model. After four months of implantation, the sensorimotor function and histological assessments revealed that the 3D printed TPU conduits promoted the regeneration in critical-sized peripheral nerve defects equivalent to autografts. This study proved that TPU-based 3D printed nerve guidance conduits can be created to replicate the complicated features of natural nerves that can promote the regeneration of peripheral nerve defects and also show the potential to be extended to several other tissues for regenerative medicine applications.

Intramuscular Pulsed Radiofrequency Upregulates BNDF-TrKB Expression in the Spinal Cord in Rats as an Alternative Treatment for Complicated Pain.

Two cases of complicated pain exist: posterior screw fixation and myofascial pain. Intramuscular pulsed radiofrequency (PRF) may be an alternative treatment for such patients. This is a two-stage animal study. In the first stage, two muscle groups and two nerve groups were subdivided into a high-temperature group with PRF at 58 °C and a regular temperature with PRF at 42 °C in rats. In the second stage, two nerve injury groups were subdivided into nerve injury with PRF 42 °C on the sciatic nerve and muscle. Blood and spinal cord samples were collected. In the first stage, the immunohistochemical analysis showed that PRF upregulated brain-derived neurotrophic factor (BDNF) in the spinal cord in both groups of rats. In the second stage, the immunohistochemical analysis showed significant BDNF and tropomyosin receptor kinase B (TrkB) expression within the spinal cord after PRF in muscles and nerves after nerve injury. The blood biomarkers showed a significant increase in BDNF levels. PRF in the muscle in rats could upregulate BDNF-TrkB in the spinal cord, similar to PRF on the sciatica nerve for pain relief in rats. PRF could be considered clinically for patients with complicated pain and this study also demonstrated the role of BDNF in pain modulation. The optimal temperature for PRF was 42 °C.

Adductor and Sciatic Peripheral Nerve Catheters for Schatzker VI Tibial Plateau Fracture: A Case Report.

Peripheral nerve blocks are typically avoided for high-speed tibial plateau fractures due to their ability to mask the paresthesias and pain associated with the feared complication of acute compartment syndrome (ACS). We present a case in which sciatic nerve and adductor canal catheters were placed utilizing low-volume infusions allowing for neurovascular assessment. These catheters served as a valuable portion of the multi-modal pain regimen in this patient with a Schatzker VI tibial plateau fracture.

Surgical Lumbar Sympathectomy in Mice.

Peripheral nerve injuries are common, and full functional recovery after injury is achieved in only 10% of patients. The sympathetic nervous system plays many critical roles in maintaining bodily homeostasis, but it has rarely been studied in the context of peripheral nerve injury. The extent of postganglionic sympathetic neuronal functions in distal targets in the periphery is currently unclear. To better explore the role of sympathetic innervation of peripheral targets, a surgical "knock-out" model provides an alternative approach. Although this can be achieved chemically, chemical destruction of postganglionic sympathetic neurons can be nonspecific and dose-dependent. The use of a surgical lumbar sympathectomy in mice, once thought to be "virtually not practicable" in small animals, allows for specific targeting of postganglionic sympathetic neurons that innervate the hind limbs. This manuscript describes how to surgically remove the L2-L5 lumbar sympathetic ganglia from a mouse as a survival surgery, which reliably decreases the hind paw sweat response and the number of sympathetic axons in the sciatic nerve.

Evaluation of the regeneration process of the sciatic nerve of a mouse animal model after application of freezing, crushing or electrocoagulation damage / Ocena procesu regeneracji nerwu kulszowego mysiego modelu zwierzecego po zastosowaniu uszkodzenia metoda mrozenia, zmiazdzenia i elektrokoagulacji.

The problem of regeneration of damaged peripheral nerves is an ongoing topic and has long been the subject of intensive research worldwide. This study examined the morphological and functional evaluation of the regeneration process within the damaged sciatic nerve, a mouse animal model. The effect of impaired expression of the TSC-1 gene on the process of nerve regeneration was evaluated, depending on the mode of damage. The research object consisted of 48, 2-month-old male TSC lines. The test group consisted of animals that underwent damage to the sciatic nerve by crushing, freezing and electrocoagulation, while the control group includes mice whose sciatic nerve was not damaged. Behavioral tests were conducted to evaluate the functional return of the limb, after 3,5,7 and 14 days. The first changes in the regeneration process of the damaged neurite are observed as early as day 3 after the injury, while on day 14 after the injury the functional return of the damaged limb was noted.

Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

OBJECTIVE: To investigate the effect of sevoflurane on neuropathic pain induced by chronic constriction injury (CCI) of sciatic nerve in mice, and to elucidate its mechanism by animal experiments. METHODS AND RESULTS: Thirty-two C57BL/6 mice were randomly divided into four groups: Sham group, Model group, Control group and Sevoflurane group. First, a mouse model of neuropathic pain was established. Then, the mice in each group were killed on Day 14 after operation to harvest the enlarged lumbosacral spinal cord. In contrast with the Model group, the Sevoflurane group displayed a significantly increased paw withdrawal mechanical threshold (PWMT) and significantly prolonged paw withdrawal thermal latency (PWTL) from Day 5 after operation. The morphological changes of lumbosacral spinal cord were observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. Pathological results showed that sevoflurane reduced nuclear pyknosis in lumbosacral spinal cord tissue, with a large number of mitochondrial crista disappearance and mitochondrial swelling. The results of Western blotting showed that sevoflurane significantly decreased the protein expressions of phosphorylated phospholipase Cγ (p-PLCγ), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and phosphorylated inositol 1,4,5-triphosphate receptor (p-IP3R), and reduced the protein expressions of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 (GRP78) and GRP94, oxidative stress-related proteins P22 and P47 and inflammatory factors nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α). CONCLUSIONS: Sevoflurane inhibits neuropathic pain by maintaining ER stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

Photosealed Neurorrhaphy Using Autologous Tissue.

Photochemical sealing of a nerve wrap over the repair site isolates and optimizes the regenerating nerve microenvironment. To facilitate clinical adoption of the technology, we investigated photosealed autologous tissue in a rodent sciatic nerve transection and repair model. Rats underwent transection of the sciatic nerve with repair performed in three groups: standard microsurgical neurorrhaphy (SN) and photochemical sealing with a crosslinked human amnion (xHAM) or autologous vein. Functional recovery was assessed at four-week intervals using footprint analysis. Gastrocnemius muscle mass preservation, histology, and nerve histomorphometry were evaluated at 120 days. Nerves treated with a PTB-sealed autologous vein improved functional recovery at 120 days although the comparison between groups was not significantly different (SN: -58.4 +/- 10.9; XHAM: -57.9 +/- 8.7; Vein: -52.4 +/- 17.1). Good muscle mass preservation was observed in all groups, with no statistical differences between groups (SN: 69 +/- 7%; XHAM: 70 +/- 7%; Vein: 70 +/- 7%). Histomorphometry showed good axonal regeneration in all repair techniques. These results demonstrate that peripheral nerve repair using photosealed autologous veins produced regeneration at least equivalent to current gold-standard microsurgery. The use of autologous veins removes costs and foreign body concerns and would be readily available during surgery. This study illustrates a new repair method that could restore normal endoneurial homeostasis with minimal trauma following severe nerve injury.

End-to-side neurorrhaphy in the reconstruction of peripheral segmental neural loss: an experimental study.

PURPOSE: To evaluate the effects on peripheral neural regeneration of the end-to-side embracing repair technique compared to the autograft repair technique in Wistar rats. METHODS: Fifteen male Wistar rats were divided into three groups with five animals each: denervated group (GD), autograft group (GA), and embracing group (EG). For the evaluation, the grasping test, electroneuromyography (ENMG), and muscle weight assessment were used. RESULTS: Muscle weight assessment and ENMG did not show significant neural regeneration at the end of 12 weeks in the DG and GE groups, but only in GA. The grasping test showed an increase in strength between the surgery and the fourth week in all groups, and only the GA maintained this trend until the 12th week. CONCLUSIONS: The present study indicates that the neural regeneration observed in the end-to-side embracing neurorrhaphy technique, in the repair of segmental neural loss, is inferior to autograft repair in Wistar rats.

GCPII Inhibition Promotes Remyelination after Peripheral Nerve Injury in Aged Mice.

Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.

Fully biodegradable and self-powered nerve guidance conduit based on zinc-molybdenum batteries for peripheral nerve repair.

Peripheral nerve injury (PNI) poses a significant public health issue, often leading to muscle atrophy and persistent neuropathic pain, which can drastically impact the quality of life for patients. Electrical stimulation represents an effective and non-pharmacological treatment to promote nerve regeneration. Yet, the postoperative application of electrical stimulation remains a challenge. Here, we propose a fully biodegradable, self-powered nerve guidance conduit (NGC) based on dissolvable zinc-molybdenum batteries. The conduit can offer topographic guidance for nerve regeneration and deliver sustained electrical cues between both ends of a transected nerve stump, extending beyond the surgical window. Schwann cell proliferation and adenosine triphosphate (ATP) production are enhanced by the introduction of the zinc-molybdenum batteries. In rodent models with 10-mm sciatic nerve damage, the device effectively enhances nerve regeneration and motor function recovery. This study offers innovative strategies for creating biodegradable and electroactive devices that hold important promise to optimize therapeutic outcomes for nerve regeneration.

rTMS applied to the PFC relieves neuropathic pain and modulates neuroinflammation in CCI rats.

The study aimed to assess the analgesic effect of 10 Hz repetitive transcranial magnetic stimulation (rTMS) targeted to the prefrontal cortex (PFC) region on neuropathic pain (NPP) in rats with chronic constriction injury (CCI) of the sciatic nerve, and to investigate the possible underlying mechanism. Rats were randomly divided into three groups: sham operation, CCI, and rTMS. In the latter group, rTMS was applied to the left PFC. Von Frey fibres were used to measure the paw withdrawal mechanical threshold (PWMT). At the end of the treatment, immunofluorescence and western blotting were applied to detect the expression of M1 and M2 polarisation markers in microglia in the left PFC and sciatic nerve. ELISA was further used to detect the concentrations of inflammation-related cytokines. The results showed that CCI caused NPP in rats, reduced the pain threshold, promoted microglial polarisation to the M1 phenotype, and increased the secretion of pro-inflammatory and anti-inflammatory factors. Moreover, 10 Hz rTMS to the PFC was shown to improve NPP induced by CCI, induce microglial polarisation to M2, reduce the secretion of pro-inflammatory factors, and further increase the secretion of anti-inflammatory factors. Our data suggest that 10 Hz rTMS can alleviate CCI-induced neuropathic pain, while the underlying mechanism may potentially be related to the regulation of microglial M1-to-M2-type polarisation to regulate neuroinflammation.