Search Results (153)

Oligodendrocytes (OLs) are specialized glial cells essential for the formation and maintenance of the myelin sheath within the central nervous system (CNS). Historically, OLs were considered a functionally homogeneous population. However, the advent and widespread application of single-cell and single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) technologies since 2015 have revealed substantial transcriptional heterogeneity, varying according to developmental stage, anatomical region, and disease state. In this review, we synthesized current advances in the understanding of OL heterogeneity. Nine OL cell classes have been identified in the mouse somatosensory cortex and hippocampal CA1 region, later expanding to 13 distinct subpopulations across ten CNS regions. Furthermore, we characterized disease-associated oligodendrocytes (DAOs)/disease-associated oligodendrocyte lineages (DOLs), identified in various neurological diseases, including multiple sclerosis (MS), Alzheimer’s disease (AD), and spinal cord injury, focusing on their molecular markers, spatial distribution, and pathophysiological roles. We summarized key transcriptional regulatory networks underlying DAO induction, including the signal transducer and activator of transcription (STAT)/interferon regulatory factor (IRF) family, the Yin Yang 1 (YY1)/nuclear factor kappa B (NF-κB) axis, and the SOX9/SOX10 regulatory system. The utility of region-specific brain analyses using spatial transcriptomics (ST) in conjunction with these approaches was also discussed. Finally, we compiled the implications of patient stratification according to white matter glial response patterns derived from large-scale snRNA-seq analyses of patients with progressive MS. Our synthesis shows that oligodendrocytes consist of multiple distinct subtypes that vary across development, brain regions, and disease conditions. In pathological states, they adopt specific disease-associated programs that reflect context-dependent responses and may influence disease progression and repair. This work provides a framework for understanding how oligodendrocyte diversity contributes to neurological disease and may support the development of targeted remyelination therapies. Full article

Traumatic injuries often result in nerve tissue damage and functional deficits due to limited regeneration. Silk fibroin, a biopolymer with inherent biocompatibility and tunable properties, is a promising material for 3D-bioprinted neural tissue scaffolds. This review highlights recent advancements in silk-derived composite scaffolds, often incorporating additional materials like collagen or conductive polymers to enhance their performance. This review examines how material composition, scaffold architecture, and fabrication strategy influence biological response and functional recovery. This comprehensive review follows PRISMA guidelines and uses comprehensive searches of PubMed, MEDLINE, Embase, Web of Science, Cochrane Central, and ClinicalTrials.gov for studies published through 2025. Studies were screened for eligibility based on substance type, mechanical properties, production methods, and outcomes. Findings were synthesized qualitatively. Twelve studies were included, comprising rat (50%), canine (8.3%), and in vitro (41.7%) models. Analysis reveals that silk fibroin acts as a highly adaptable mechanical backbone. It can consistently integrate with bioactive additives (collagen, dECM) or conductive polymers (Polypyrrole, MXene) to meet specific therapeutic demands. For spinal cord injuries, composites reached a compressive modulus capable of resisting physiological pressures and preventing scaffold collapse. In soft tissue applications, silk–hydrogel blends provided localized release of exosomes and small molecules during the acute injury phase, reducing neuroinflammatory markers. Additionally, adding conductive materials allowed the scaffolds to bridge electrical gaps and promote Schwann cell proliferation and neuronal differentiation. Furthermore, 3D bioprinting enabled the creation of defined microchannels that replicate native fascicular architecture. In vivo outcomes consistently showed superior axonal regeneration, myelination, and synaptic reconnection compared to controls, correlating with significant improvements in electrophysiological and motor function. This review highlights the clinical potential of silk fibroin-based 3D-printed biomaterials for nerve regeneration, including neural repair and neural tissue engineering. More recent studies place greater emphasis on integrating mechanical, architectural, and biological considerations into scaffold design, resulting in increasingly multifunctional scaffold systems. Despite promising efficacy, the heterogeneity of fabrication methods and the predominance of rodent models highlight the need for standardized protocols and evaluations in relevant models to facilitate clinical translation. Full article

Following traumatic injury, nerve repair is essential to the restoration of muscle function and sensation. The current gold standard of nerve repair is microsuture repair, which requires trained microsurgeons to perform time-intensive and technically demanding procedures under high magnification. Microsuture repair suffers from inconsistent repair quality among surgeons and variable clinical outcomes. Neurorrhaphy sutures are non-resorbable and prone to fibrous tissue ingrowth and attendant foreign body reaction, both of which are believed to contribute to the observed shortfall in clinical outcomes. Here, we introduce a novel, sutureless, in situ forming, and fully degradable hydrogel coaptation device for nerve repair. The practical usability of the hydrogel device was assessed by procedure timing, tensile repair strength, and repair quality compared to the traditional microsuture approach. Human cadaveric nerves were used to perform hydrogel and suture repairs for comparison in a relevant model. Additionally, the hydrogel coaptation device was used for primary sciatic nerve repairs in rats to assess feasibility for use in nerve repair in vivo. We observed that hydrogel nerve repairs were performed nearly three times faster than microsuture repairs, without any significant difference in tensile strength when pulled to failure, and had favorable quality scores when blindly assessed by plastic surgeons. Histologically, the in vivo feasibility study showed nerve bridging visualized using H&E, neurofilament, and myelin staining. Our findings suggest the novel hydrogel coaptation device may serve as a potential alternative to suture repair, with features addressing several critical limitations inherent to microsuture and existing nerve repair methods. Full article

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) characterized by persistent inflammation, demyelination, and progressive neurodegeneration, driven largely by aberrant activation of T and B lymphocytes that infiltrate the CNS and cause myelin and axonal damage, leading to neurological impairment. Although current therapies broadly suppress immune activity and reduce relapse rates, their effects on neurodegenerative processes remain limited. Also, the safety profile of disease-modifying therapies (DMTs) may become problematic, especially in older patients with comorbidities and/or advanced disability. Emerging data suggest that opioid signaling may exert immunomodulatory, remyelinating, and neuroprotective effects, representing a novel and underexplored therapeutic avenue. Given that current MS therapies primarily target inflammation but fail to promote myelin repair or prevent neurodegeneration, opioid signaling emerges as a novel and underexplored pathway with potential benefits for immunomodulation and remyelination, as well as possible neuroprotective effects. Despite concerns about classical opioid-related adverse effects, accumulating evidence shows that opioid-mediated interventions have been associated with reduced inflammatory activity, attenuation of demyelination, and enhanced neuronal survival and have shown therapeutic benefit in MS. Although current findings are largely preclinical, they provide a compelling rationale for further investigation of the opioid system as a potential adjunctive or novel therapeutic strategy. Full article

Disease-modifying therapies (DMTs) are the standard treatment for multiple sclerosis (MS) and effectively reduce inflammatory disease activity; however, their effects on neurodegeneration, remyelination failure, and long-term symptom burden vary across disease stages and patient populations. Adjunctive non-DMT approaches have therefore been investigated to target biological processes not primarily addressed by conventional immunomodulatory treatment. These strategies often involve agents originally developed for non-neurological indications, whose mechanisms of action extend beyond their primary clinical use and may intersect with pathways relevant to MS pathophysiology. This narrative review summarizes pharmacological agents, nutraceuticals, and selected bioactive compounds evaluated as adjunctive interventions in MS, with emphasis on immunometabolic regulation and remyelination-related mechanisms. Evidence from experimental models, translational studies, and clinical trials is examined to assess repurposed drugs and metabolic modulators with reported effects on immune responses, glial function, and myelin repair. Particular emphasis is placed on the distinction between mechanistic rationale and clinical outcomes, highlighting the challenges of translating biologically plausible effects into consistent therapeutic benefit. Available data indicate that most adjunctive strategies do not demonstrate consistent disease-modifying effects, although some interventions influence specific biological pathways relevant to neuroinflammation, cellular metabolism, and oligodendrocyte biology. Reported outcomes vary according to disease stage, treatment duration, and selected clinical or imaging endpoints. Overall, adjunctive non-DMT strategies remain investigational and require further evaluation in biologically stratified clinical studies. 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

Braided nerve guidance conduits (NGCs) composed of decellularized porcine small intestinal submucosa (SIS) were developed to achieve an appropriate balance between mechanical performance and biological compatibility for peripheral nerve repair. This study aimed to compare four SIS-braided conduits with silicone tubes in terms of bending compliance, tensile strength, swelling behavior, and cytocompatibility. SIS-braided conduit exhibited a favorable combination of flexibility, tensile strength, and dimensional stability. In vitro evaluations using PC12 and SW10 cells demonstrated that SIS-braided conduit supported neurite outgrowth and Schwann cell adhesion, confirming its favorable cytocompatibility. Based on these findings, SIS-braided conduits and silicone tubes were subsequently evaluated in a rat sciatic nerve defect model. Functional recovery assessed using the Sciatic Functional Index suggested preliminary functional recovery in the SIS-braided conduit, and histological analyses revealed evidence of axonal regeneration and myelin formation within the conduit. Overall, the results indicate that the integration of mechanical robustness with biological activity is essential for the design of nerve graft substitutes. The conduit braided from decellularized small intestinal submucosa represents a promising biodegradable alternative, a considerable biodegradable alternative to conventional non-degradable silicone conduits for peripheral nerve repair. Full article

Intracerebral hemorrhage (ICH) remains a devastating condition with no available therapies that can effectively mitigate secondary injury and promote neurological repair. This research presents a novel combinatorial regenerative strategy, concurrently delivering adipose-derived stromal vascular fraction (SVF) within an adhesive self-assembling peptide (HGF-RADA16-IKVAV) nanohydrogel (HGF). In a clinically relevant rat model of ICH with hematoma evacuation, the combined therapy of HGF and SVF demonstrated synergistic and enhanced efficacy. In the short term, the combined therapy demonstrated hemostatic benefits, and significantly reduced hematoma volume, brain edema, neuronal apoptosis and neuroinflammation indicated by pro-inflammatory markers (NLRP3, caspase-1, Iba-1, CD68, GFAP) while increasing the levels of anti-inflammatory (CD206) and angiogenic (CD31) markers. Longitudinal behavioral assessments conducted over six weeks demonstrated persistent and significant improvements in motor coordination, forelimb strength, and gait parameters within the HGF + SVF group, surpassing all monotherapies. Ultrastructural analysis also showed that myelinated axons were better preserved at the injury border, with thicker myelin sheaths. These findings demonstrate that the co-administration of SVF with an adhesive and hemostatic hydrogel collaboratively diminishes secondary injury, modulates neuroinflammation, and promotes functional and structural brain recovery following ICH, indicating a promising and translatable strategy. Full article

Low-intensity pulsed ultrasound (LIPUS) has emerged as a versatile, non-invasive physical modality with growing potential in regenerative medicine and neural repair. Advances in ultrasound physics and biomedical engineering have enabled precise spatiotemporal control of acoustic stimulation, positioning therapeutic ultrasound as an alternative to conventional pharmacological and surgical interventions that often suffer from limited targeting and substantial side effects. Unlike high-intensity focused ultrasound, which relies primarily on thermal ablation, LIPUS operates within a low-energy, non-thermal regime and modulates cellular behavior through mechanical cues, mechano-transduction, and downstream biological responses. Accumulating evidence demonstrates that LIPUS regulates calcium dynamics, cytoskeletal remodeling, neurotrophic factor expression, inflammation, myelination, and local vascular remodeling, thereby promoting functional recovery in both peripheral and central nerve injury models. Moreover, the integration of LIPUS with biomaterials, including piezoelectric scaffolds and acoustically responsive drug delivery systems, has expanded its functionality from direct stimulation to on-demand electrical signaling and controlled therapeutic release. Despite these advances, challenges remain regarding parameter standardization, mechanistic consistency, and clinical translation. In this review, we summarize the systems, parameters, and biological mechanisms underlying LIPUS, discuss its applications in peripheral and central nerve injury repair, and highlight emerging strategies and translational barriers toward intelligent, multimodal, and personalized ultrasound-based therapies. Full article

ATP-binding cassette A1 (ABCA1) is a critical molecule in facilitating cholesterol transport in a variety of organs. In the nervous system, cholesterol supply is essential and rate-limiting for myelin biogenesis, which underlies efficient conduction of nerve impulses. When myelin is damaged or improperly formed due to genetic defects, a host of neurological symptoms may arise. A rare form of peripheral neuropathy in Tangier disease (TD) patients is associated with autosomal recessive mutations in ABCA1. Accordingly, when ABCA1 loses its function due to misexpression, the neuropathic phenotype is over-represented. Independently, studies have revealed the altered expression of ABCA1 and dysregulation of cholesterol metabolism in a host of inherited peripheral neuropathies engaging the Peripheral Myelin Protein 22 (PMP22), suggesting shared pathophysiology. While the role of ABCA1 has not been investigated broadly in peripheral nerves, the transporter molecule is a therapeutic target for human disorders, including multiple sclerosis and Alzheimer’s disease. Investigations in rodent models of type 1 Charcot–Marie–Tooth (CMT) neuropathies support the candidacy of this cholesterol transporter as a therapeutic target in efforts of peripheral myelin repair. Ongoing preclinical studies in central and peripheral nervous system disease models will provide critical information on the importance of ABCA1 as a target for disease modifying intervention. Full article

Background: Peripheral nerve injury can happen for a variety of causes. Despite major breakthroughs in microsurgery, nerve repair results are not always sufficient. Methods: Thirty-two Wistar albino rats were split into four groups: primary nerve repair (PNR), PNR with vitamin D3 treatment, nerve crush injury (NCI), and NCI with vitamin D3 treatment. In the PNR + D3 and NCI + D3 groups, 1 mcg/kg of vitamin D3 was given intraperitoneally on days 1, 3, 5, and 7 of the 12-week healing period. Electrophysiological measurements were taken prior to the injury. At 12 weeks after damage, a hot plate test was performed to assess acute pain, and the electrophysiological measurements were repeated. Before the rats were sacrificed, biopsy samples from the right sciatic nerve were collected for histopathological evaluation. Results: Post-healing action potential values were not statistically different between the PNR and PNR + D3 groups; however, they were considerably lower in the NCI + D3 group than in the NCI group. The reaction time in the hot plate test was considerably slower in the D3-treated groups compared to the control groups. Histopathology score was substantially higher in the PNR + D3 group as compared to the PNR group, and lower in the NCI + D3 group as compared to the NCI group. Conclusions: Other than improved myelination, vitamin D3 treatment following primary repair of transected nerves produced no statistically significant improvement. Vitamin D3 treatment caused a negative impact on the crush injury, as assessed by the findings of histopathology and electrophysiological measurements. Overall, the results indicate that the efficacy of vitamin D3 treatment may vary depending on the type of injury. Full article

Background: Peripheral nerve regeneration relies on Schwann cell activation and neurotrophic support. Although adipose-derived stem cells (ADSCs) show therapeutic potential through paracrine mechanisms, their clinical application is often limited by donor-dependent heterogeneity in therapeutic efficacy. Accordingly, strategies to standardize and potentiate their secretory function are essential. This study investigated a safety-optimized strategy to achieve this by combining three-dimensional (3D) spheroid culture with ibudilast, a clinically approved phosphodiesterase inhibitor. Methods: Human ADSCs were cultured in 2D or 3D conditions with varying ibudilast concentrations. Safety was confirmed via CCK-8 assays, and trophic factor secretion was quantified by RT-qPCR and ELISA. To rigorously validate functional outcomes, conditioned media were applied to a dual-model system comprising immortalized rat (RSC96) and primary human Schwann cells (HSwCs), assessing migration and the expression of regeneration-associated genes. Results: Ibudilast demonstrated no cytotoxicity. While 3D culture alone enhanced secretion compared to 2D controls, the addition of ibudilast provided a synergistic boost, resulting in a 6- to 14-fold increase in NGF, VEGF, and IGF-1 levels compared to 3D spheroids alone. Notably, conditioned media from these primed spheroids significantly accelerated HSwCs migration and induced robust upregulation of myelination-related genes (specifically PMP22 and EGR2), with trophic effects sustained for up to 72 h. Conclusions: Ibudilast-primed 3D spheroids synergistically amplify the neuroregenerative secretome of ADSCs. By utilizing a repurposed, safe small molecule to overcome functional variability and maximize potency without genetic manipulation, this strategy represents a highly translatable candidate for peripheral nerve repair. Full article

Multiple sclerosis (MS) pathogenesis involves not only immune-mediated myelin injury but also glial responses. We examined how three charge isomers of myelin basic protein (MBP)—native (C1), phosphorylated (C4), and citrullinated (C8)—modulate rat astrocytes. Cytokines were quantified and grouped (pro/anti-inflammatory, chemotactic, neurotrophic, angiogenic, tissue remodeling), and regulatory markers assessed. C1 strongly upregulated the lipid-sensing receptor LXR, and reduced global DNA methylation; C4 moderately enhanced LXR; C8 failed to activate LXR or alter methylation. Functionally, C1 attenuated IL-1β, IL-6 and GM-CSF while increasing IL-10 and certain chemokines. C4 elicited an intermediate pattern, inducing CX3CL1 (fractalkine), CCL20, VEGF-A and TIMP-1 with minor effects on classical cytokines. In contrast, C8 triggered a robust pro-inflammatory phenotype, increasing IL-1α/β, TNF-α and GM-CSF, with higher IL-10, fractalkine, CCL20, VEGF-A and TIMP-1. All isomers suppressed IFN-γ, IL-4 and CNTF. These data indicate that MBP post-translational modifications drive distinct astrocyte phenotypes through integrated cytokine, metabolic and epigenetic pathways: C1 favors immune regulation and repair, C4 blends inflammatory and reparative cues, and C8 amplifies neuroinflammation. Understanding how modified MBP shapes astrocyte behavior provides mechanistic insight into lesion evolution in MS and suggests astrocyte-directed strategies to modulate neuroinflammation and promote remyelination. Full article

Peripheral nerve repair remains a major clinical challenge, and novel strategies such as conduit-assisted repair have been developed to improve outcomes. In this study, we fabricated a 3D-printed nerve guidance conduit (NGC) composed of polycaprolactone (PCL), a biocompatible and biodegradable polymer, combined with acellular dermal matrix (ADM) derived from porcine dermis, in order to create a multilayered PCL–ADM NGC with both favorable mechanical properties and biological activity. Twenty rabbits were divided into four groups: a negative control group, a silicone tube repair group, an autologous nerve graft group, and a group treated with the 3D-printed PCL–ADM NGCs. Sciatic nerve regeneration was assessed at 4 and 12 weeks postoperatively using electrophysiological measurements, histological staining, and electron microscopy. The PCL–ADM NGC demonstrated comparable axonal regeneration and functional recovery to autologous grafting, and it significantly outperformed silicone tubes in terms of axonal count and maximal electrophysiological response. Histological and ultrastructural analyses further confirmed that the PCL–ADM NGC facilitated organized regeneration with dense myelinated axons and reduced degenerative changes. The fabricated NGCs exhibited excellent flexibility without compromising lumen diameter, which is critical for adapting to the physiological environment of peripheral nerves. These findings indicate that combining synthetic polymers with biologically derived matrices can enhance the regenerative microenvironment and overcome limitations of traditional synthetic conduits. In conclusion, the 3D-printed PCL–ADM NGC represents a promising alternative to both silicone tube repair and autologous nerve grafting by providing structural support and bioactivity while reducing the need for donor nerve harvesting. Further studies in larger animal models and longer follow-up periods will be required to confirm long-term efficacy and support clinical translation of this technology. Full article

Demyelinating diseases comprise a group of chronic and debilitating neurological disorders, with the destruction of the myelin sheath serving as the core pathological hallmark. The central pathogenesis involves immune-mediated damage to oligodendrocytes (Ols) and myelin breakdown, accompanied by a vicious cycle of neuroinflammation and impaired epigenetic repair. Current therapeutic strategies, including conventional immunomodulatory agents to targeted monoclonal antibodies, effectively control disease relapses but exhibit limited efficacy in promoting neural repair. Consequently, research focus is increasingly shifting towards neuroprotective and remyelination strategies. In this context, Emerging therapeutic promise stems primarily from two fronts: the advent of novel pharmaceuticals, such as remyelination-promoting drugs targeting oligodendrocyte maturation, interventions inhibiting epigenetic silencing, signal pathway inhibitors, and natural products derived from traditional Chinese medicine; the development of innovative technologies, including cell therapies, gene therapy, exosome and nanoparticle-based drug delivery systems, as well as extracellular protein degradation platforms. Nevertheless, drug development still faces challenges such as disease heterogeneity, limited blood–brain barrier penetration, long-term safety, and difficulties in translating findings from preclinical models. Future efforts should emphasize precision medicine, multi-target synergistic therapies, and the development of intelligent delivery systems, with the ultimate goal of achieving a paradigm shift from delaying disability progression to functional neural reconstruction. Full article