搜索结果：Neural regeneration research

Spinal cord injury (SCI) causes irreversible neurological deficits and represents a major global health and socioeconomic burden. Although neural progenitor cell (NPC) transplantation is strongly supported by preclinical evidence through cell replacement, intrinsic neuroregeneration, and broad neurotrophic and immunomodulatory effects, its clinical translation has progressed more slowly than anticipated. In parallel, rapid advances in gene editing, biomaterial engineering, and organoid technologies are reshaping the therapeutic landscape. Therefore, it is timely to systematically re-evaluate the current evidence on NPC-based therapies for SCI and to refine future translational strategies. This review provides an updated and comprehensive overview of NPC therapy for SCI across the full translational continuum. First, we summarize the biological properties, advantages, and limitations of NPCs derived from adult or embryonic neural tissues, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), highlighting issues such as tumorigenicity, immune responses, and manufacturing standardization. We then focus on efficacy-oriented genetic modifications and engineered delivery systems, including NPCs overexpressing neurotrophic, synaptogenic, or pro-survival factors, as well as combination strategies integrating NPCs with biomaterials, small molecules, or immunomodulatory agents to enhance graft survival, circuit reconstruction, and motor and sensory recovery. Subsequently, we systematically analyze 19 clinical trials of NPC/NSC-based products conducted in 10 countries, covering HuCNS-SC, LCTOPC1, NSI-566, hESC-OPC, and the emerging iPSC-derived product XS228. Trial designs, dosing regimens, routes of administration, safety profiles, and preliminary functional outcomes are compared, and key design principles for next-generation clinical trials and patient selection are proposed. Finally, we discuss organoid-based approaches and artificial intelligence (AI)-assisted decision tools as emerging platforms for disease modeling, protocol optimization, and precision indication refinement. NPC-based therapy for SCI remains at an early but promising translational stage. No NPC product has yet achieved regulatory approval, reflecting persistent challenges in cell source optimization, safety control, graft survival, in vivo tracking, and trial design. Nevertheless, by integrating rigorous cell source selection, rational gene modification, advanced delivery systems, and well-designed clinical trials targeting carefully defined patient populations, NPCs are expected to achieve meaningful-and potentially transformative-clinical benefits for individuals with SCI in the future.

Neurological injuries remain a major clinical challenge due to the limited regenerative capacity of neural tissue, the persistence of inhibitory post-injury microenvironments, and the lack of biomaterials capable of simultaneously providing structural support and biological instruction. Growing evidence highlights that biomaterial-mediated modulation of the neural microenvironment is essential for effective neural regeneration and functional recovery. Silk fibroin (SF), a naturally derived protein biomaterial, has attracted growing interest in neural repair owing to its tunable mechanical properties, controllable degradation, structural anisotropy, and versatile modification potential. Beyond serving as passive scaffolds, SF-based biomaterials actively regulate axonal guidance, neural and glial cell behavior, and neuroinflammatory responses. This review systematically summarizes the physicochemical properties and modification strategies of SF, elucidates the underlying mechanisms by which SF-based materials promote neural repair, and discusses diverse SF-based material formats, including hydrogels, scaffolds, patches, nanofibers, and nerve conduits. Representative applications in peripheral nerve injury and central nervous system disorders, such as spinal cord injury, traumatic brain injury, cerebral palsy, ischemic stroke, and Parkinson's disease, are highlighted. Finally, current challenges and future perspectives of SF-based neural biomaterials are discussed, with an emphasis on guiding the rational design and clinical translation of next-generation neural repair strategies.

The neural crest (NC) is a transient, multipotent cell population that contributes extensively to vertebrate embryogenesis, generating craniofacial structures, peripheral nerves, melanocytes, and cardiovascular elements. While classically studied in the context of development, increasing evidence demonstrates that NC-derived cells persist into adulthood, where they support tissue homeostasis, plasticity, and repair. This review synthesizes current insights into the lifelong impact of the NC, with emphasis on aging, degeneration, and regeneration. We first outline the developmental origins and lineage diversification of NC cells, highlighting mechanisms that establish long-lived progenitor pools. We then examine how age-related changes in NC-derived tissues, including craniofacial bone remodeling, pigmentary alterations, autonomic decline, and peripheral neuropathies, reflect broader principles of cellular senescence and disrupted signaling. The involvement of NC derivatives in age-associated pathologies, such as neurodegeneration, cardiac anomalies, and craniofacial degeneration, is also addressed. Finally, we highlight progress in regenerative medicine that leverages NC-derived stem and progenitor cells, together with molecular pathways that may rejuvenate their function in aging tissues. By integrating developmental, pathological, and regenerative perspectives, this review positions the NC as a central contributor to organismal aging and underscores its translational relevance. We also outline unresolved questions and future research directions at the interface of NC biology, aging, and regenerative medicine.

Stroke is the second leading cause of death globally and a major contributor to long-term disability. Neural stem cells (NSCs) offer a promising therapeutic strategy for ischemic conditions by modulating neuroinflammation, enhancing neuroplasticity, facilitating tissue remodeling, and promoting neural tissue regeneration. Preclinical evidence strongly indicates that NSCs migrate to damaged brain regions and play a crucial role in repair by differentiating into various functional neural cell types. Recent research has underscored the significance of specific molecular pathways, particularly the Wnt/β-catenin and Notch signaling pathways, in determining NSC fate. These pathways are essential for orchestrating key intracellular transcription factor expression and for regulating mechanisms that govern NSC function. They influence the secretion of critical factors from both NSCs and the surrounding cells, exhibiting opposing effects on neuronal differentiation and cellular fate. This dual nature of signaling pathways is vital for synchronizing the expression of proneural genes while also regulating fundamental processes such as self-renewal, differentiation, and growth in response to hypoxic or ischemic conditions. This review aims to elucidate the intricate signaling mechanisms that govern NSC fate after ischemic stroke, with a focus on the Notch and Wnt/β-catenin pathways. A deeper understanding of these mechanisms could pave the way for new therapeutic interventions that significantly enhance structural integrity, promote neural repair, improve functional recovery, and maintain brain homeostasis in stroke patients.

Brain injury refers to a state in which the brain cannot function due to an abnormality in the nerve tissue from internal or external causes. However, existing treatments for brain injury are largely unable to promote neural regeneration or reverse structural damage. In contrast, stem cell-based approaches provide a significant potential for repairing such injuries. This study conducted a bibliometric visualization analysis using tools such as CiteSpace, VOSviewer, and Scimago Graphica, based on 8785 relevant publications indexed in the Web of Science Core Collection (WoSCC) from 2009 to 2025. A total of 8785 publications were included in this study. The number of publications in this area showed a significant linear growth trend. China and the United States were the core research nations. The University of California System and Harvard University were the main research institutions. Michael Chopp and Cesar V. Borlongan were the core high-output scholars. Extracellular vesicles (EVs), exosomes, and neuroinflammation represented the most prominent research directions at present. This study reveals the knowledge structure, distribution of research capabilities, and developmental trajectory in the field of stem cell therapy for brain injury. It provides data support and decision-making references for scientific planning, interdisciplinary collaboration, and clinical translation in this domain.

The retina and optic nerve rely on a tightly regulated neurovascular unit that sustains the highly dynamic and metabolically demanding neural tissues required for vision. Adequate oxygen and nutrient delivery are essential for maintaining tissue function and cellular survival. Over the past decades, extensive research within and beyond the field of ophthalmology has sought to elucidate the mechanisms that govern neurovascular regulation in health and disease. Growing evidence indicates that neurovascular dysfunction plays an important role in both the initiation and progression of glaucoma, a leading cause of irreversible blindness worldwide. Alterations in vascular architecture and blood flow may compromise the metabolic support required by retinal ganglion cells, increasing their vulnerability to injury and degeneration. While neurons possess limited regenerative capacity, the vascular system retains a remarkable degree of plasticity and is therefore amenable to repair. This vascular plasticity presents an opportunity to develop therapeutic strategies aimed at restoring vascular architecture and improving blood flow, complementing existing approaches focused on intraocular pressure reduction, neuroprotection, axonal regeneration, and/or neuronal transplantation. In this review, we summarize the current understanding of neurovascular function in the healthy eye, discuss mechanisms that contribute to vascular compromise in glaucoma, and highlight emerging avenues for promoting vascular regeneration and blood flow recovery. By identifying key knowledge gaps and future research priorities, we aim to outline promising directions for targeting the ocular neurovasculature to preserve retinal ganglion cell function and slow or stop progressive vision loss.

Axon regeneration in the central nervous system (CNS) remains limited, imposing severe constraints on functional recovery after injury. Here, we reveal that the deubiquitinase OTU deubiquitinase 7 A (OTUD7A) critically regulates CNS regeneration by modulating histidine triad nucleotide-binding protein 1 (HINT1) stability. OTUD7A stabilizes HINT1 protein through specific removal of K63-linked ubiquitin chains at lysine 7. Screening of the small-molecule deubiquitinase inhibitor PR-619 identified HINT1 as a key ubiquitination-regulated target. Notably, genetic knockdown of Hint1 alone was sufficient to improve RGC survival and promote optic nerve regeneration, thereby activating mTOR signaling, while PR-619 administration enhanced tissue preservation and axon repair after spinal cord injury. A multi-gene therapeutic strategy further enhanced optic nerve regeneration in the optic nerve crush (ONC) model. These findings identify the OTUD7A-HINT1-mTOR axis as a potential therapeutic target in CNS regeneration.

Despite understanding the pathophysiology of Alzheimer's disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA's therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.

Physical models aimed to reproduce basic features of the solar sunspot cycle are typically based on the solar dynamo mechanism. Usually qualitative arguments are used to define parameters of the model, among which a challenging component is the nonlinear form of quenching of the α effect governing regeneration of the magnetic field. We propose an approach, in which the functional form of the α quenching is represented by a neural network model embedded into neural differential dynamo equations trained on observational data. For demonstration, we consider a low-mode dynamo model and find a wide set of α-quenching functions and corresponding dynamo numbers that provide an accurate fit to the average profile of the solar cycle data given by sunspot numbers. Within this set, we observe a strong relationship between the dynamo number and the shape of the α-quenching function indicating that additional magnetic field data or constraints are essential to unambiguously infer parameters of the dynamo model. In our opinion, the neural differential approach opens a prospect for data-driven investigation of the closure problem in dynamo theory.

The phylum Cnidaria is the outgroup of Bilateria and includes sea anemones, corals, hydroids, and jellyfish. Cnidarians play crucial ecological roles in marine ecosystems, including the formation of highly diverse and productive coral reefs, and acting as important predator and prey species. They are also well known for their remarkable regeneration capacities. Here, we report single-cell RNA sequencing of bell tissue remodelling/regeneration after amputation in two species of scyphozoans or 'true jellyfish', the Asian moon jelly, Aurelia coerulea and the flame jellyfish, Rhopilema esculentum. We delineated 12 cell populations in Aurelia and Rhopilema and revealed their respective marker genes and enriched gene pathways. During this process, conserved transcription factor Otx, TFAP2A, Erg, NFIA and Wnt/β-catenin signalling pathway genes were identified. Additionally, we discovered two conserved, sequentially activated patterns, with putative proliferative cells, gastrodermal cells, neural cells, and secretory gland cells modulated in the first phase, followed by cnidocytes in the second phase. Further comparison among cnidarian genomes identified a suite of lineage-specific scyphozoan genes, a subset of which were frequently significantly expressed in cnidocytes in both jellyfish species. Using powerful single-cell RNA sequencing approaches, this study elucidates the evolution of lineage-specific genetic networks and biological processes in true jellyfish, which remain comparatively poorly studied, and in particular provides key insights into the molecular pathways underlying their remarkable regenerative capacity.

Spinal cord injury (SCI) is a debilitating disorder of the central nervous system and remains a major challenge in neural regeneration and rehabilitation research. Spinal cord stimulation (SCS) has demonstrated notable efficacy in promoting neural repair and functional recovery following SCI. Its mechanisms include enhancing descending pathway conduction through neural plasticity, suppressing inflammation, and stimulating the secretion of neurotrophic factors, thereby creating a permissive microenvironment for axonal regeneration and remyelination. Nevertheless, in cases of complete SCI or extensive structural damage, SCS alone often shows limited therapeutic benefits. Advances in materials science have introduced conductive biomaterials as a promising strategy for SCI repair. These materials can replicate the spinal cord's electrical microenvironment, fill lesion sites, promote neural stem cell differentiation, guide directional axonal growth, facilitate remyelination, and modulate immune responses to mitigate secondary injury, collectively contributing to neuroprotection and functional recovery. This review systematically summarizes recent progress in the application of SCS and conductive biomaterials for SCI repair, highlights the current limitations of SCS in clinical settings, and provides an in-depth discussion on the mechanisms and translational potential of conductive biomaterials in neural regeneration.

Spinal cord injury remains difficult to treat because of the intrinsically limited regenerative capacity of neurons. Although neural progenitor cell (NPC) therapies are promising, inadequate graft survival, uncontrolled differentiation and weak functional integration continue to restrict outcomes. Here we report biohybrid microrobots called NPCbots, fabricated by integrating human-induced pluripotent-stem-cell-derived NPCs with magnetoelectric nanoparticles, enabling wireless magnetic navigation and non-invasive neuronal stimulation. A lab-on-a-chip platform allows scalable fabrication and maintains cell viability and differentiation capacity. In a zebrafish spinal cord injury model, alternating magnetic field stimulation of NPCbots induced rapid in vivo neuronal and astrocytic differentiation, enhanced graft integration at the lesion site, and near-complete recovery of swimming and exploratory behaviours within 3 days. In a non-regenerating murine model of complete spinal cord transection, NPCbots were well tolerated for at least 28 days, localized effectively to the injury site, promoted neural differentiation and resulted in substantial improvements in motor function within 4 weeks. These results demonstrate that magnetically guided NPCbots combined with non-invasive magnetoelectric stimulation promote neural repair and functional recovery in preclinical spinal cord injury models.

To review recent research progress on nerve transfer for the reconstruction of upper limb function following peripheral nerve injury and central nervous system injury. A retrospective analysis of recent domestic and international literature on nerve transfer was conducted. The evolution of nerve transfer surgery from its application in peripheral nerve injuries to its extension to central nervous system injuries was described. The current therapeutic status of nerve transfer in upper limb hemiplegia resulting from spinal cord injury and brain injury was discussed, and the central role of central nervous system plasticity in postoperative functional recovery was analyzed. Nerve transfer is a crucial technique for upper limb function reconstruction, initially used to treat peripheral nerve injuries such as brachial plexus injuries. In recent years, this technique has gradually expanded into the field of central nervous system injuries. In cervical spinal cord injuries, various nerve transfer procedures can restore elbow flexion, wrist extension, and hand grasping functions, with efficacy correlated with the activation of plasticity in the spinal cord distal to the injury site. In cases of upper limb hemiplegia following brain injury, contralateral C 7 nerve transfer is the primary procedure, which can significantly reduce muscle tone and improve partial motor function; however, its ability to enhance fine motor skills and key muscle strength remains limited, and challenges such as maladaptive plasticity and co-activatory patterns persist. Mechanisms of central plasticity involve interhemispheric reorganization, activation of cortico-red nucleus-spinal pathways, and the remodeling of sensorimotor networks. The expansion of nerve transfer techniques from "peripheral repair" to "induction of central plasticity" offers a new strategy for treating central upper limb paralysis. However, current applications in brain injury are limited by a lack of surgical diversity and restricted central plasticity. Future efforts should integrate cell/gene therapy, electrical stimulation, novel transfer techniques, and systematic rehabilitation training to enhance neural regeneration and central plasticity, thereby further improving therapeutic outcomes. 综述神经移位术重建周围神经损伤及中枢神经系统损伤患者上肢功能的研究进展。. 回顾分析近年国内外有关神经移位术文献，阐述神经移位术从周围神经损伤拓展至中枢神经系统损伤的演变历程，重点探讨其在脊髓损伤和脑损伤偏瘫上肢中的治疗现状，并分析中枢可塑性在术后功能恢复中的核心作用。. 神经移位术是上肢功能重建的重要技术，最初用于臂丛损伤等周围神经损伤治疗，近年来已逐步拓展至中枢神经系统损伤领域。在颈髓损伤中，多种神经移位术可重建屈肘、伸腕及手部抓握功能，其疗效与激活损伤远端脊髓可塑性相关；在脑损伤偏瘫上肢中，以健侧C 7神经移位术为主，可显著降低肌张力、改善部分运动功能，但其对手部精细动作及关键肌力的提升仍有限，且存在适应不良性重塑、联合运动模式等挑战。中枢可塑性机制涉及半球间重组、皮质-红核-脊髓通路激活及感觉运动网络重塑等。. 神经移位术从“外周修复”向“诱导中枢重塑”的拓展为中枢性上肢瘫提供了新策略，但当前在脑损伤中的应用术式单一、中枢重塑受限。未来需结合细胞/基因治疗、电刺激、新型移位术式及系统性康复训练，以增强神经再生与中枢可塑性，进一步提升疗效。.

Neural stem cells (NSCs) span a continuum of cellular states that share fundamental properties with their differentiated glial progeny. Recent single-cell studies have refined our understanding of the diversity within both NSC and glial populations, revealing a highly dynamic and interconnected landscape of cell identities. In this review, we examine the glial nature of NSCs, emphasizing their heterogeneity and the stem- and progenitor-like properties shared with the differentiated glia. We focus particularly on astrocytes and integrate evidence from invertebrate models demonstrating that glial cells possess an intrinsic capacity for neurogenesis. Together, these findings highlight areas of convergence between astrocyte plasticity and NSC-associated properties, with important implications for nervous system regeneration and brain cancer.

This review aims to provide a comprehensive overview of graphene-based quantum dots (GBQDs) in oral healthcare, focusing on their physicochemical properties tailored to the oral microenvironment, their applications in dental disease management, current research limitations, and future perspectives for clinical translation. systematic literature search was conducted in PubMed, Web of Science, and Scopus for publications from the last 15 years up to February 2026. Keywords included "graphene quantum dots", "graphene oxide quantum dots", "dentistry", "oral", "antibacterial", "tissue regeneration", "oral cancer", and "dental materials". Manual searching of reference lists was also performed. From 401 initially identified records, 49 studies underwent full-text review, and 20 representative studies were included based on their relevance to the oral microenvironment and scientific contribution to the field. Studies were categorized into four key areas: antibacterial applications, tissue regeneration, oral cancer therapy, and dental material modification. GBQDs exhibit unique properties such as nanoscale dimensions, tunable fluorescence, high surface area for drug loading, and multimodal antibacterial mechanisms, which make them particularly suitable for the complex oral environment. Current applications span infectious disease management, tissue regeneration, oral cancer theranostics, and dental material enhancement. However, challenges remain in expanding applications beyond current focus, understanding microbial interactions, and achieving vascular and neural regeneration. Future efforts should prioritize disease-specific design, multi-species inhibition strategies, and clinical translation. This scoping review provides clinicians and researchers with a comprehensive understanding of GBQDs' potential in dentistry, highlighting the role in targeted drug delivery, antimicrobial therapy, tissue engineering, and diagnostic imaging, thereby informing future clinical applications and research directions in nanodentistry.

Long noncoding RNA (lncRNA) Pnky is a trans-acting regulator of neural stem cell (NSC) differentiation, but the molecular mechanisms by which Pnky regulates neurogenesis are unknown. A fundamental step toward mechanistic understanding is to determine whether lncRNA structure underlies biological function. Using chemical probing and high-throughput analysis, we determined the secondary structure of Pnky folded in vitro and in cellulo. In vitro-transcribed Pnky RNA adopts a compact, highly structured conformation with evidence of tertiary interactions. In cellulo,Pnky secondary structure is similar to the in vitro conformation. We used locked nucleic acid (LNA) oligonucleotides to interrogate the entire Pnky transcript for function in NSCs and identified regions that when targeted increase neurogenesis-phenocopying Pnky knockdown-without decreasing transcript abundance. Our findings implicate specific structured regions of Pnky in the regulation of neurogenesis and illustrate how structural maps combined with phenotypic data can advance our understanding of lncRNA function.

This paper examined the removal of Acid Yellow 36 (AY36), Methyl Red (MR), and Methylene Blue (MB) dyes using a novel Ammonia-decorated Red Algae Biochar (RAB-A) synthesized from red algae (Pterocladia capillacea) via a reflux technique in the presence of 25% ammonium hydroxide (NH4OH). The physicochemical properties of the synthesized RAB-A, including its surface area, morphology, functional groups, elemental composition, and thermal stability, were comprehensively characterized through Brunauer-Emmett-Teller (BET) analysis, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) integrated with energy-dispersive X-ray (EDX) analysis, and thermogravimetric analysis (TGA). RAB-A demonstrated a low specific surface area (3.262 m2/g) and a monolayer adsorption capacity of 0.7495 cm3 (STP)/g. The adsorbent demonstrated an overall pore volume of 0.011 cm³/g, accompanied by an average pore diameter of 13.648 nm. Thermogravimetric analysis revealed an overall mass loss of 40.84% for RAB-A, demonstrating enhanced thermal stability relative to RAB, which showed a weight loss of 51.05%. FTIR analysis confirmed the presence of diverse functional moieties on the surface of RAB-A. Adsorption experiments targeting Acid Yellow 36 (AY36), Methyl Red (MR), and Methylene Blue (MB) were conducted in batch mode by independently adjusting the initial dye concentration (100-200 mg/L), contact time (5-180 min), solution pH (2-12), and adsorbent dosage (0.5-1.5 g/L). The adsorption equilibrium behavior was best described by the Langmuir isotherm, which indicated maximum uptake capacities of 222.22 mg/g for AY36, 192.31 mg/g for MR dye, and 833.33 mg/g for MB dye. Kinetic analyses revealed that the adsorption of all examined dyes was best described by a pseudo-second-order model, thereby demonstrating the high suitability of the synthesized RAB-A for the efficient elimination of dyes from aqueous solutions. Additionally, adsorption was predicted and adjusted utilizing artificial neural networks (ANN).

The regulatory network of the spleen, a densely innervated immune hub, undergoes pathological remodeling following spinal cord injury. Whether targeted electrical stimulation of the spleen at specific frequencies can reverse peripheral immune suppression or improve the central immune system remains unclear. The aim of this study was to elucidate the previously unexamined effects and differential regulatory mechanisms of transsplenic apex electrical stimulation (10, 50, and 100 Hz) on peripheral immune suppression and spinal cord homeostasis after spinal cord injury. A mouse model of T3 spinal cord injury was established and systematically evaluated through functional assessments, splenic/spinal cord transcriptome sequencing, weighted gene co-expression network analysis, Short Time-series Expression Miner analysis, and multiomics validation to investigate the frequency-dependent effects of stimulation. The effects of the electrical stimulation exhibited significant frequency dependence. Specifically, 100 Hz electrical stimulation effectively restored the impaired bacterial clearance capacity in the host (P < 0.001), reversed the suppression of adaptive immune-related gene modules in the spleen, and shifted immune responses toward T helper 17 (Th17) cell-axis remodeling. This was accompanied by upregulation of the expression of key hub genes such as those encoding integrin alpha x, CC chemokine receptor 6, Fc receptor-like 5, leukocyte immunoglobulin-like receptor subfamily A member 5, and Th17 signature cytokines such as interleukin-17, interleukin-23, and transforming growth factor-beta. In the spinal cord, 100 Hz electrical stimulation suppressed pro-inflammatory pathways such as nuclear factor-kappa B and tumor necrosis factor-alpha while activating neurorepair pathways, such as glutamatergic synapses. In contrast, 10 Hz electrical stimulation failed to alleviate peripheral immune suppression and exacerbated splenic immunosuppression and central neuroinflammation. These findings demonstrate that electrical stimulation of the splenic apex exerts frequency-dependent, bidirectional modulatory effects, with 10 and 100 Hz eliciting contrasting neuroimmune responses. Specifically, 100 Hz electrical stimulation activates the splenic Th17 immune axis, offering a potential mechanism to reverse spinal cord injury-induced immunodeficiency and neurological damage. Identifying the stimulation frequency as a critical therapeutic variable provides a foundation for developing frequency-optimized integrated neuroimmunomodulatory strategies for the treatment of spinal cord injury.

Intervertebral disc (IVD) degeneration (IVDD) is a major cause of low back pain, yet treatment options remain limited. Robust IVDD models are essential for discovering and validating new regenerative treatments. Ex vivo whole organ bioreactor cultures using bovine IVDs are a well-established approach, with various degeneration models developed on this platform. However, most existing models replicate only isolated aspects of IVDD, failing to reflect its complex nature. There is a critical need for in vitro models that more accurately simulate the full spectrum of degeneration phenotypes observed in patients. Combining multiple well-established degeneration models offers a promising strategy. In this study, we investigated the combined effects of enzyme (papain) and cytokine (tumor necrosis factor alpha [TNF&#x3b1;]) based degeneration inducers on bioreactor loaded bovine IVDs. While papain injection led to a 5.5-fold higher glycosaminoglycan loss and tissue void formation, TNF&#x3b1; induced inflammatory and catabolic changes relevant to IVDD, including significant aggrecanase-1 (ADAMTS4) upregulation and a 2.65-fold increase in interleukin 6 release. Both effects were evident when combined, enabling the manifestation of multiple aspects of IVDD in one model. To also explore implications on nociception, primary bovine dorsal root ganglion neurons were cultured and treated with conditioned medium from the induced degenerative IVDs. Nociceptors treated with degenerative medium showed a 1.51-fold higher proportion of neurons with a response compared to treatment with control IVD medium. By expanding the range of degenerative changes and bridging them to pain-associated features, this model provides a valuable platform for testing novel regenerative therapies.