Search Results (602)

Background: Carpal tunnel syndrome (CTS) is the most prevalent peripheral nerve entrapment neuropathy, with rising incidence in aging populations. Uncertainty persists regarding the efficacy and safety of carpal tunnel release (CTR) in patients aged ≥ 70 years. Objectives: To systematically evaluate the indications, clinical outcomes, and utility of CTR in elderly patients (≥70 years), with comparison to younger cohorts. Methods: Following PRISMA 2020 guidelines, PubMed/MEDLINE, Scopus, CENTRAL, Embase, Web of Science, and grey literature sources were searched from inception through September 2025. Two independent reviewers extracted data; inter-rater agreement was strong (κ = 0.81–0.86). The primary outcome was the Boston Carpal Tunnel Questionnaire (BCTQ). Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using DerSimonian–Laird random-effects models. Certainty of evidence was assessed using the GRADE framework. Results: A total of 20 studies encompassing 3841 operated hands, including 1139 hands in elderly patients and 2702 hands in younger comparators across comparative studies, were analyzed. Mean SS-BCTQ improvement was 1.8 points (95%CI: 1.6–2.0; exceeding the established MCID of 1.04–1.05 points). FS-BCTQ improvement was 1.1 points (95%CI: 0.9–1.3; marginally below the pooled MCID of 1.13 points). Elderly patients demonstrated SS-BCTQ improvement of 1.7 points and satisfaction rates of 72–94%, comparable to younger cohorts (75–95%; p = 0.38). Grip strength improved 15–25% in younger patients but remained unchanged in elderly patients (p < 0.001). Sensory recovery reached 42% in elderly versus 58% in younger patients (p < 0.01). Complication rates were low and age-independent (3.1%; RR 1.08; 95%CI: 0.86–1.35; p = 0.52). GRADE certainty was as follows: low for symptom and functional improvement; very low for surgery versus conservative management. Conclusions: CTR is associated with significant symptomatic benefit in elderly patients when conservative treatment fails, with complication rates comparable to younger populations. Age alone should not constitute a surgical contraindication. Preoperative counseling must establish realistic expectations regarding grip strength and functional recovery. High-quality randomized trials in elderly populations remain an urgent research priority. Full article

Artificial nerve guidance conduits (NGCs) have gained significant attention in the field of peripheral nerve regeneration for the treatment of critically sized nerve defects. Nanotechnology-based NGCs are being explored as potential solutions for repairing and reconstructing peripheral nerve injuries due to their unique structure and topography. In this study, we present a novel core–sheath GelMA/PCL nanofiber construct fabricated through electrospinning and phase separation methods. The core–sheath GelMA/PCL nanofibers replicate the topological morphology of the native extracellular matrix (ECM). The outer layer, composed of GelMA, serves as an “adhesion domain” facilitating direct interaction with surrounding cells and tissues while improving wettability, integrin-mediated cell adhesion/attachment, and degradation. PCL, acting as the “elastic domain” within the nanofibers, enhances mechanical properties, maintains long-term stability of the NGCs, and enables controlled release of GelMA. Histomorphometric analysis along with electrophysiological and behavioral assessments demonstrate that these core–sheath GelMA/PCL nanofiber-based NGCs can activate endogenous mechanisms for peripheral nerve repair while promoting sensory/motor nerve regeneration and functional recovery. Overall, our findings demonstrate that GelMA/PCL nanofibers within the nuclear sheath can effectively remodel the nerve regeneration microenvironment by integrating “mechanical- biochemical” signals, thereby offering a novel strategy for addressing critical-size nerve defects. Full article

Recent advancements in biology and medicine have facilitated the progress of nerve regeneration that markedly improves the treatment of peripheral nerve injuries, enhancing outcomes and recovery rates. It has been reported that erythropoietin (EPO) is currently being studied as a potential agent for neural repair. However, much evidence has confirmed that EPO treatment can induce systemic adverse effects in the clinical fields, including coronary stent thrombosis and deep vein thrombosis. Herein, a derivative of EPO without any hematopoietic activities, which is named carbamylated erythropoietin (CEPO), has been synthesized and investigated for its effects on peripheral neural repair both in vitro and in vivo. The in vitro experimental results demonstrated that CEPO enhanced Schwann cell viability, proliferation, migration, and nerve growth factor (NGF) expression, while the optimal concentration of CEPO was found to be 25 μg/mL. The in vivo observations at 21 days post-injection indicated that the CEPO group exhibited a significant functional improvement in the sciatic nerve injury model, guiding regrowing axons across the injury site. Thus, CEPO serves as a promising candidate or adjunctive strategy for peripheral nerve injuries, demonstrating promising clinical applications and potential for enhancing Schwann cell viability, proliferation, and migration, as well as anticipated nerve axon development. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Peripheral nerve blocks can effectively reduce the use of general anesthesia and opioids in situations where robust pain management is critical, such as severe extremity trauma and hip, femur, and knee surgeries. Despite these benefits, nerve blocks are underutilized due to the high skill required to accurately insert a needle and safely deliver local anesthetic. To overcome this challenge, ultrasound image guidance enabled by artificial intelligence (AI) offers a semi-automated solution for regional anesthesia delivery by non-specialists. As a first step towards realizing an integrated platform for AI-guided nerve blocks, the main objective of this study is to develop and characterize deep learning algorithms to interpret anatomical landmarks on ultrasound images in real time and identify aimpoints for needle placement. Our AI system was trained on over 55,000 images from 20 porcine models and demonstrated an average area under the precision–recall curve of 0.92 (SD = 0.03) for in vivo landmark detection in the femoral nerve region. In prospective live animal testing, aimpoint identification had a 98.3% success rate with an average time of 40.5 s (SD = 33.5). Future work will focus on integrated testing with handheld robotics towards a more accessible method for delivering regional anesthesia in settings from point of injury to medical transport to hospitals. Full article

Background/Objectives: While the functions of angiotensin-converting enzyme (ACE) 1 and 2 are well established in peripheral tissues, the role of the spinal ACE1 and ACE2 pathways in the development of neuropathic pain remains unclear. This study examined the role of the spinal ACE1 and ACE2 pathways in trigeminal neuropathic pain produced by inferior alveolar nerve (IAN) injury. Methods: The experiments were conducted using male Sprague-Dawley rats (6–8 weeks old, weighing 220–250 g). The left mandibular second molar was extracted, and a dental mini-implant was placed to induce IAN injury. IAN injury produced robust and long-lasting mechanical allodynia and markedly increased angiotensinogen (AGT) expression within the ipsilateral trigeminal subnucleus caudalis (iTSC). Results: Neuropathic mechanical allodynia was inhibited by intracisternally administered losartan (an angiotensin II type-1 receptor antagonist), but not by an angiotensin II type-2 receptor antagonist. Intracisternal treatment with captopril (an ACE1 inhibitor) and diminazene aceturate (an ACE2 activator) produced significant anti-allodynic effects. Intracisternally injected angiotensin-(1-7) reduced neuropathic mechanical allodynia, and this anti-allodynic effect was blocked by pretreatment with A779, a Mas receptor inhibitor. In naïve rats, the intracisternal administration of DX600 (an ACE2 inhibitor) resulted in mechanical allodynia, which was inhibited by intracisternal pretreatment with losartan. IAN injury led to upregulated ACE1 expression and downregulated ACE2 expression in the iTSC. Conclusions: Our findings indicate that IAN injury induces a polarized shift in the ACEs within the iTSC, characterized by increased ACE1 and decreased ACE2 expression. Their modulation may therefore offer a promising strategy for developing effective treatments for chronic pain. Full article

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. Full article

Peripheral nerve injuries cause profound medical and socioeconomic consequences. Despite substantial microsurgical advances, including nerve autografting, nerve transfers, and the commercial availability of effective conduits, functional recovery remains incomplete for most patients. Current outcomes underscore the need for novel adjunctive therapies capable of enhancing axonal regeneration, accelerating reinnervation, and mitigating denervation-induced target atrophy. Tacrolimus, a calcineurin inhibitor widely used in organ transplantation, has emerged as a potent immunomodulatory and neuroregenerative agent. However, its systemic use is constrained by severe dose-limiting toxicities and metabolic derangements. This limitation has driven a paradigm shift toward localized tacrolimus delivery, leveraging biomaterials to achieve therapeutic drug concentrations at the repair site while minimizing systemic toxicity. This review synthesizes the state-of-the-art advances in biomaterial-based tacrolimus local delivery systems. We highlight biological mechanisms underlying tacrolimus-mediated neuroregeneration and immunomodulation. Engineering strategies including nerve conduits, wraps, injectable hydrogels, electrospun scaffolds, and stimuli-responsive carriers are discussed, with attention to polymeric composition, fabrication technologies, degradation kinetics, and pharmacological performance. We also explored the regulatory, manufacturing, and scalability challenges inherent to drug–device combination products. Finally, we identify emerging directions including multimodal biomaterials that integrate tacrolimus with trophic factors, extracellular vesicles, or bioelectrical stimulation. Collectively, biomaterial-enabled tacrolimus delivery represents a transformative strategy to bridge traditional nerve surgical repair and functional recovery. This review provides a roadmap for future interdisciplinary innovation at the interface of biomaterials science, neurobiology, pharmacology, and surgery. Full article

Spinal cord stimulation (SCS) has expanded beyond pain treatment, becoming a neuromodulatory method capable of recruiting spinal and supraspinal circuits involved in motor recovery. This review summarises mechanistic knowledge, supports engineering developments, and describes the changing clinical translation of SCS in rehabilitation. Mounting scientific data shows that SCS’s effects go beyond dorsal column modulation and may involve segmental networks that promote activity-dependent plasticity and sensorimotor pathway restoration, probably due to a combination of Hebbian and non-Hebbian mechanisms (synaptic potentiation, interneuronal reorganisation, and altered afferent–efferent coupling). More recent advances, such as bursts and the high-frequency paradigm, closed-loop control, and data-driven parameter optimisation methods, improve the precision, stability, and calibration of stimulation for each individual. By combining SCS with non-invasive forms of neuromodulation (TMS, tDCS, and peripheral nerve stimulation), one can potentially further intensify corticospinal plasticity and maintain improvements in functions. Spinal cord stimulation remains an established treatment for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome. In recent years, however, increasing attention has been directed toward its potential role in motor recovery after spinal cord injury and stroke. Progress in this area is limited by patient heterogeneity, variability in outcome measures, the complexity of multimodal rehabilitation protocols, and regulatory and logistical constraints—particularly when adaptive or closed-loop systems are used. Current evidence suggests that motor-restorative applications of SCS should be interpreted cautiously and integrated within carefully designed rehabilitation programmes, with attention to patient selection and realistic expectations regarding the durability of the benefit. Full article

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research. Full article

Background/Objectives: Self-mutilation behavior is often triggered by neuropathic pain associated with peripheral nerve injuries (PNIs). Polyethylene glycol (PEG)-fusion is a repair method that rapidly joins/fuses the open ends of closely apposed severed axons, greatly reduces Wallerian degeneration, and restores sensorimotor behavior much more rapidly than current clinical procedures. Here, we examined whether the improved sensorimotor behavior recovery following PEG-fusion repair of sciatic nerve injuries compared to Negative Controls (NC) correlated with self-mutilation. We also examined six variables (repair method, behavioral tests, sex, injury type, strain, and surgical experience) that could influence self-mutilation outcomes. Methods: The Sciatic Functional Index (SFI) and the Von Frey (VF) behavioral tests were performed and analyzed. Regression and other analyses were performed to determine the independent effect of six variables on self-mutilation rates and severity. Results: PEG-fused rats that had no self-mutilation had significantly better SFI scores than those that had self-mutilation. More rapid VF sensory recovery in PEG-fused rats was also associated with less self-mutilation. Self-mutilation rates and severity were: (1) significantly reduced following PEG-fusion repairs compared to NCs; (2) significantly increased following weekly VF tests; (3) not different between female and male rats or (4) between simple transection and segmental-loss PNIs; (5) non-existent in Lewis rats and significantly less severe in Sprague Dawley rats than Long Evans rats; and (6) significantly reduced in rats operated on by experienced PEG-fusion surgeons who historically achieved better SFI outcomes than trainee surgeons. Conclusions: Our data suggest potential clinical benefits of PEG-fusion repair to produce more rapid and better sensorimotor recoveries and reductions of self-mutilation behaviors. Full article

Peripheral nerve injuries involving critical-sized gaps remain a major clinical challenge. Although autologous nerve grafting is considered the gold standard for peripheral nerve repair, its clinical application is limited by the availability of donor nerve tissue and the risk of donor-site morbidity, including sensory deficits and functional impairment. Therefore, nerve guidance conduits (NGCs) have emerged as a promising alternative when combined with bioactive modulation strategies. In this study, we evaluated bisvinyl sulfonemethyl (BVSM)-crosslinked gelatin conduits integrated with electrical stimulation (ES) at different frequencies (0, 2, 20, and 200 Hz) in a rat sciatic nerve defect model over a 4-week recovery period (n = 10 per group). Structural regeneration was assessed by morphometric analysis, electrophysiology, macrophage infiltration, CGRP immunoreactivity, retrograde Fluorogold tracing, quantitative PCR of growth factors and inflammatory cytokines, and behavioral testing. Among all stimulation paradigms, low-frequency ES at 2 Hz produced the most pronounced regenerative effects. The 2 Hz group demonstrated significantly greater axon number, axonal density, and regenerated nerve area compared with control and high-frequency groups (p < 0.05). Electrophysiological assessments revealed improved nerve conduction velocity, higher MAP amplitudes, and shorter latencies. Enhanced macrophage recruitment and elevated CGRP expression were observed, suggesting coordinated neuroimmune and neurochemical activation. Gene expression analysis indicated upregulation of neurotrophic factors and balanced inflammatory cytokine responses under low-frequency stimulation. In contrast, high-frequency stimulation (200 Hz) failed to enhance overall regeneration and showed reduced axonal metrics, suggesting possible overstimulation-associated suppression. Collectively, these findings demonstrate that BVSM-crosslinked conduits provide a stable and biocompatible regenerative scaffold, and that appropriately tuned low-frequency electrical stimulation (2 Hz) optimally enhances structural, molecular, and functional recovery. The integration of material engineering with bioelectrical modulation represents a promising strategy for next-generation bioelectronic interfaces in peripheral nerve repair. Full article

Background/Objectives: Stereotactic body radiation therapy (SBRT) provides improved pain response and local control for spinal metastases. However, management of local failure after initial SBRT is challenging. We report institutional outcomes, dosimetry, and toxicity for reSBRT following SBRT. Methods: We retrospectively reviewed 61 lesions (55 patients) treated with reSBRT after prior SBRT. Both SBRT courses delivered a median dose of 27 Gy. Patients underwent clinical and radiological evaluation every three months. Toxicity was graded using CTCAE v5.0. Dosimetric parameters for the spinal cord (SC), cauda equina (CE), planning organ-at-risk volumes (PRV), and thecal sac were converted to equivalent dose in 2 Gy fractions (EQD₂) using the linear–quadratic model (α/β = 2). Results: Median follow-up was 10.3 months. Forty lesions (65%) were cervicothoracic and 21 (35%) were lumbosacral. One- and two-year overall survival (OS) were 45% and 29%, respectively, and one- and two-year local control (LC) were 89% and 88%, respectively. Gastrointestinal primary tumors were associated with inferior LC (HR 2.41, 95% CI 1.11–5.23, p = 0.026). Fifteen patients (27%) reported myelitis/neuropathic symptoms during follow-up; four (7%) developed new post-radiation myelitis or neuropathy (RMN) without radiologic progression. Five patients (9%) developed vertebral compression fractures (VCF). Cumulative EQD₂ was not significantly associated with RMN (p = 0.344); all affected patients had thecal sac EQD₂ > 95.5 Gy and relevant nerve roots EQD₂ > 108 Gy. Conclusions: ReSBRT provided a favorable LC with acceptable toxicity. High cumulative dose to the thecal sac and nerve roots may contribute to neurologic toxicity as peripheral nerve injury. Full article

Peripheral nerve injuries often lead to incomplete recovery despite surgical repair. Vitamin B12 and folic acid have been implicated in nerve regeneration, but their comparative effects have not been systematically evaluated. Twenty-four male Wistar rats underwent femoral nerve transection and were assigned to three groups: control, vitamin B12 (2500 µg/kg weekly, subcutaneous), and folic acid (40 mg/L in drinking water). Functional recovery was assessed over eight weeks using foot-base angle (FBA) during beam walking. Histological analysis evaluated axon counts and myelination (g-ratio). Both treatments accelerated early gait recovery compared to controls, with significant FBA improvement at week 4 (p < 0.05). Vitamin B12 produced sustained functional benefits through week 8 and superior myelination (lower g-ratio, p < 0.0001), whereas folic acid increased axon numbers but did not enhance myelin thickness or late-phase recovery. High-dose vitamin B12 significantly improves structural and functional outcomes after femoral nerve injury, while folic acid primarily supports early axonal regrowth. Vitamin B12 represents a promising pharmacological adjunct for peripheral nerve repair. Further research should explore optimal dosing strategies and long-term effects in clinical settings. To our knowledge, no prior study has directly compared the effects of folic acid and vitamin B12 supplementation within the rat femoral-nerve model, providing the rationale for the present head-to-head design. Full article

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article