Background:Subaxial cervical facet dislocation (CFD) is a severe neck injury associated with head-first impact (HFI). However, CFD has not been reliably reproduced in experimental or numerical studies, limiting understanding of its underlying mechanics. This study quantified the influence of preimpact head-forward posture on lower-neck sagittal-plane loading associated with CFD during HFI. Methods:A detailed finite element head-neck model was enhanced and evaluated against literature data, then used to investigate HFI response at a 2 m/s vertical drop impact velocity. A reposturing procedure achieved graded head-forward eccentricity from 0 to 50 mm in 5 mm increments, reflecting postures observed during anticipatory neck bracing. A matched cadaveric HFI experiment was subsequently performed with 30 mm eccentricity. Results:Simulations demonstrated that eccentricities of 15 mm or more produced an S-shaped neck deformation during impact, as observed in prior experiments that produced CFD, accompanied by marked increases in anterior intervertebral shear and flexion bending at C7/T1. The matched cadaveric experiment produced bilateral C7/T1 dislocation, consistent with the predicted loading and deformation trends. However, complete CFD was not reproduced computationally because current intervertebral soft-tissue failure formulations did not capture the observed failure progression. Conclusions:Preimpact head-forward eccentricity can substantially increase lower-neck loading and susceptibility to CFD under the inverted-drop conditions studied.
Background:The Neurocore-SENSED framework, derived from a three-round modified Delphi process involving 77 international spine surgeons, provides a structured reference standard for reporting in endoscopic spine surgery (ESS) for disc disease. The ability of large language models (LLMs) to reproduce graded levels of expert agreement within a reporting framework has not been examined in ESS. Objective:To evaluate the extent to which three contemporary LLMs align with the Neurocore-SENSED consensus and whether they discriminate between items of differing consensus level. Methods:In January 2026, each of the 166 framework items with published item-level endorsement data was submitted once to GPT-5.2, Gemini 3 Pro, and Claude Sonnet 4.6, in independent sessions with web retrieval disabled. Models selected one of five ordered response options directly. Alignment was assessed by Spearman correlation with panel endorsement and by four measures of categorical agreement, each with bootstrap 95% confidence intervals. Separate protocols examined response stability, response format, and prior exposure to the consensus. Results:All three models correlated significantly with panel endorsement. Gemini 3 Pro aligned most closely (r s = 0.709, 95% CI 0.627-0.776), exceeding Claude Sonnet 4.6 (r s = 0.622; p = 0.009) and GPT-5.2 (r s = 0.565; p < 0.001), which did not differ. Categorical agreement was limited and equivalent across models, with observed agreement of 0.506-0.518 and overlapping confidence intervals for all marginal-robust statistics. Between 81.3% and 95.8% of responses fell in the top two categories, and discordance was almost entirely unidirectional: 31 items were endorsed by every model but by fewer than half the panel, against one item in the opposite direction. Weighted kappa was not interpretable in this setting. Conclusion:Current LLMs reproduce the broad rank ordering of expert endorsement in ESS reporting but cannot reliably distinguish endorsed from contested propositions, principally because of a positive response bias.
The intervertebral disc is a prime example of tissue adaptation to metabolic and mechanical extremes. As the largest avascular organ in the human body, the disc and the central nucleus pulposus (NP) endure constant compressive loading while sustaining a hypoxic, relatively acidic, and hyperosmotic microenvironment that would be inhospitable to most cell types. Over the past two decades, work from my laboratory has revealed extraordinary details of this type of adaptation, that hypoxia-inducible factors (HIFs), particularly HIF-1α, serve as master regulators of NP cell survival, metabolism, and matrix homeostasis. This review chronicles the scientific and personal journey that began with a single unexpected observation: the normoxic stabilization of HIF-1α in NP cells. That finding grew into a substantial understanding of oxygen-independent HIF regulation and biology in the disc. Through sustained collaborations with Irving Shapiro and other colleagues and a succession of talented trainees, we demonstrated that HIF-1α is indispensable for disc development and homeostasis. In contrast, HIF-2α plays a distinct, largely opposing role, promoting matrix catabolism and fibrosis. Our work has revealed the molecular architecture underlying the disc's adaptation to avascularity, encompassing HIF-dependent regulation of glycolytic enzymes, glucose transporters, carbonic anhydrases CA9 and CA12, monocarboxylate transporter 4 (MCT4), and BNIP3-mediated mitophagy, and has opened promising therapeutic avenues for disc regeneration. Recently, we discovered that NP-derived lactate exported via MCT4 is actively imported primarily by vertebral endplate cells, and, to a lesser extent, by annulus fibrosus cells via MCT1, where it serves dual roles as a TCA metabolite and an epigenetic regulator through lactylation. This review celebrates the intellectual journey, the collaborative spirit that sustained it, and the honor of the Alexander von Humboldt Research Award, while providing a synthesis of HIF biology in the intervertebral disc spanning the discovery of oxygen by Priestley 1774 to the 2019 Nobel Prize and beyond.
Background:Adolescent idiopathic scoliosis (AIS) is the most common three-dimensional spinal deformity, predominantly affecting females aged 10-16 years. Although no single etiological factor has been definitively identified, alterations in bone quality and biomechanical properties have been proposed as contributing factors to AIS development. Methods:We developed a surgical protocol to obtain trabecular bone biopsies from the apex vertebra during anterior corrective surgery for AIS. Multimodal analysis was performed on samples from eight AIS participants (14.8 ± 1.5 years), including microstructural assessment via micro-computed tomography (micro-CT), bone mineral density distribution (BMDD) via quantitative backscattered electron imaging (qBEI), and mechanical characterization via nanoindentation. Correlations with major curve angle, apical wedge angle, and Risser grade were investigated. Results:Mean trabecular bone volume fraction (BV/TV) was 0.146 ± 0.029, comparable to values reported in healthy populations. Mean trabecular thickness (Tb.Th) was 0.146 ± 0.011 mm, suggesting slightly thicker trabeculae than typically reported in healthy young cohorts. BMDD analysis revealed CaPeak values of 23.34 ± 1.02 wt% Ca, and greater CaWidth values (4.26 ± 0.33 wt% Ca) compared to healthy adolescent and adult reference data. CaPeak was significantly negatively correlated with apical wedge angle, indicating lower mineralization with increasing vertebral wedging. Nanoindentation showed a negative association between reduced modulus (13.37 ± 2.5 GPa) and apical wedge angle, with hardness values of 0.412 ± 0.079 GPa. Conclusions:These findings provide novel insights into vertebral trabecular bone alterations in AIS and their association with deformity severity. To our knowledge, this is the first study to integrate micro-CT, qBEI, and nanoindentation analyses in AIS vertebral biopsies, revealing structural, compositional, and mechanical differences that may contribute to the pathogenesis and progression of AIS.
Background:Spondylodiscitis/spondylitis is an intractable disease requiring long-term intravenous antibiotics administration. However, drug delivery is greatly restricted because of the avascular nature in the intervertebral disc, which not only delays recovery but increases antimicrobial resistance and osteomyelitis. The purpose of this study is to elucidate the efficacy of gelatin hydrogel microsphere incorporating cefazolin (GM-CEZ) using a rat spondylodiscitis model. Methods:First, GM-CEZ was characterized by in vitro degradability, sustainability, and antimicrobial effects. Second, its efficacy in vivo was evaluated using a rat spondylodiscitis model of bioluminescent methicillin-susceptible Staphylococcus aureus. Antimicrobial effects were monitored using an in vivo imaging system and blood tests. Residual bone volume was evaluated using micro-computed tomography. Immunohistology for angiogenesis-related CD31 and smooth muscle actin was also performed. Third, in vivo safety was evaluated using a rat intervertebral disc injection model with blood tests for systemic safety and TUNEL staining for local safety. Results:In vitro, CEZ was gradually released with GM degradation and antimicrobial effects increased proportionally to the degradation. In vivo, single topical injection of GM-CEZ (1 mg GM, 250 μg/kg CEZ, 100 μL collagen) significantly reduced the amount of bacteria with fewer white blood cells 7 days after treatment and bone destruction 28 days after treatment, compared to local administration of CEZ (250 μg/kg) and systemic administration of CEZ (25 mg/kg/day for 28 days) (all, p < 0.05). Immunopositivity was significantly higher in rats with local GM-CEZ administration than those with local CEZ and systemic CEZ administration (all, p < 0.05), indicating greater tissue reformation. In vivo safety experiments demonstrated no significant myelotoxicity, nephrotoxicity, and local cytotoxicity of GM-CEZ. Conclusions:The local administration of GM-CEZ using a fraction of the systemic CEZ dose achieved enhanced antimicrobial effects without systemic and local toxicity, suggesting its potential as a promising treatment strategy for pyogenic spondylodiscitis.
Background:The treatment of severe disc pathologies through lumbar interbody fusion (LIF) involves the insertion of an interbody cage into the degenerated disc space, together with a supporting fixation system. Conventional cage materials, such as Ti6Al4V and PEEK, present several limitations, most notably their non-biodegradability, increasing the risk of cage migration and long-term subsidence (up to 40% incidence). Bioceramics may represent an option while addressing the issue of biodegradability. This study preliminarily investigates the applicability of a commercial bioceramic as an interbody cage material for LIF. Methods:First, an intact L4-L5 functional spine unit (FSU) was validated under both pure moments and combined loading conditions. Subsequently, all surgical steps of the LIF procedure were simulated, followed by postoperative physiological loading to compare the mechanical performance of the ceramic device with standard titanium cages. Two surgical techniques, posterior-LIF (PLIF) and eXtreme-LIF (XLIF), were analyzed. Each simulation assessed the mechanical strength of the interbody cage, the posterior fixation, and the vertebral bone, together with the FSU kinematic. Results:The intact model accurately predicted literature-reported kinematics and intradiscal pressure, and the LIF model reproduced forces on titanium cages consistent with in vitro measurements on human specimens. Both XLIF and PLIF procedures resulted in significant kinematic stabilization of the FSU, with > 70% reduction in range of motion. For PLIF, ceramic cages sustained applied loads with no predicted failure, while XLIF showed minimal interface failure (< 0.6%). Compared with titanium, ceramic cages significantly reduced adjacent vertebral strain, lowering the subsidence risk, without overloading the posterior fixation system. Conclusion:The present study supports the potential of bioceramics as viable materials for interbody cage applications in LIF procedures. Experimental tests and clinical validation should be accompanied to further cage design optimization to enhance the safety margins of this novel bioceramic device and ensure proper clinical effectiveness.
Background:Adolescent Idiopathic Scoliosis (AIS) is a spinal deformity of unknown etiology that begins in the intervertebral disc and emerges during pubertal growth. In the vertebral growth plate, adjacent to the disc, powerful growth plate morphogens (GPMs) modulate this growth. We evaluated whether GPMs can also alter the capacity of annulus fibrosus (AF) disc cells to proliferate and/or remodel their extracellular matrix (ECM). Methods:AF cell responsiveness to seven GPMs was screened in monolayer culture by RT-qPCR for downstream signaling markers. GPMs and concentrations eliciting significant transcriptional responses were selected for deeper analysis. Bulk RNA sequencing (RNA-seq) was conducted on AF cells cultured in a 2.5D environment to preserve their native elongated phenotype. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology enrichment, focusing on ECM remodeling and cell-proliferation processes. Transcriptomic findings were corroborated by assessments of cell proliferation (DNA content), sulfated glycosaminoglycan (sGAG) levels, and matrix metalloproteinase (MMP) activity. Results:BMP-2, TGF-β1, and FGF-2 significantly altered AF cell expression of downstream target genes, whereas Ihh, PTHrP, Wnt-1, and FGF-18 did not. IGF-1 induced modest, dose-dependent gene expression changes that were not replicated by RNA-seq. BMP-2 and TGF-β1 upregulated genes associated with anabolic ECM remodeling. BMP-2 promoted a cartilage-like ECM with increased expression of type II-associated collagens, aggrecan, and hyaluronan synthesis. TGF-β1 promoted type I collagen-associated genes, collagen cross-linking, and myofibroblast activation. In contrast, FGF-2 activated transcriptional programs related to cell-cycle progression, collagen degradation, and increased GAG turnover. Functionally, we observed higher DNA content under BMP-2 and TGF-β1 stimulation and higher sGAG levels under BMP-2, TGF-β1, and FGF-2 treatment. Conclusion:BMP-2, TGF-β1, and FGF-2 can modulate AF cell behavior, influencing tissue remodeling and implicating their involvement in disc wedging during AIS onset.
Background:Cervical arthrodesis is a common surgical technique utilized to treat many cervical spinal pathologies. The risk of re-operation due to symptomatic adjacent segment disease (ASD) remains steady, and the cause of ASD, whether rigid fixation or disease progression, remains unknown. The purpose of this study was to develop a cervical fusion model and analyze motion of the subaxial cervical spine adjacent segments following single level, two-level, and three-level spine fusion. Methods:A in vitro cervical arthrodesis biomechanics model was developed utilizing nine fresh-frozen cervical spine specimens. Each spine underwent non-destructive testing in flexion, extension, axial rotation, and lateral bending using a six degree-of-freedom robotic manipulator. Following intact specimen testing, testing was repeated after C5-C6, C4-C6, C5-C7, C4-C7 fusions. Changes in range of motion among tests were calculated at each segment. Results:The cervical arthrodesis model showed reduced motion significantly at all fused levels. Following single level fusion at C5-C6, no statistically significant increases in adjacent segment motion occurred in any testing condition (p > 0.05). Fusion between C4-C6 resulted in increased motion during flexion at C2-C3 (p < 0.001). Two-level fusion between C5-C7 resulted in increased flexion at C2-C3 (p < 0.001) and C4-C5 (p < 0.05). Lastly, three-level fusion from C4-C7 produced significant changes in extension at C2-C3 (p < 0.01), C3-C4 (p < 0.01), and C4-C5 (p < 0.01), in flexion at C2-C3 (p < 0.01) and C4-C5 (p < 0.001), right axial rotation at C2-C3 (p < 0.001) and left axial rotation at C2-C3 (p = 0.001), C3-C4 (p < 0.02), and C4-C5 (p < 0.001). Conclusion:We successfully developed a rigid cervical arthrodesis model and tested specimens in single, two-level, and three-level cervical fusion. No increases were found in adjacent segments following single level fusion and non-contiguous motion was increased following C4-6 fusion. Three-level fusion showed the greatest change in adjacent segment motion.
Background:The intervertebral disc serves a critical role in spine function, but with aging and degeneration the disc undergoes changes that alter disc mechanics, and degeneration is often implicated in low back pain. The objective of this study was to quantify and evaluate the impact of aging and degeneration on in vivo lumbar disc mechanics across the lifespan. Methods:Repeated MRI was performed at a reference state and three loading states: flexion, extension, and diurnal loading for 84 subjects (evenly distributed by sex and age group from 18 to 83 years old). Intervertebral disc deformations were evaluated between the reference and loading states by change in wedge angle, anterior-posterior (A-P) Shear displacement, and axial strain. Results:Flexion induced the greatest changes in the lower discs of young subjects, but this shifted toward the central discs in older subjects. Flexion induced a gradient of anterior shear displacement in the upper levels and posterior shear displacement in the lower levels that was maintained across all ages. Extension had opposite trends in A-P shear displacement with respect to level, with young subjects having greater posterior shear displacement at L1-L2 and greater anterior shear displacement at L5-S1 than older subjects. Extension also had large changes in wedge angle between L1 and L3. Diurnal loading consistently induced compression across all disc regions. Diurnal change in disc height was age-dependent, with greater disc height loss in younger subjects. Conclusions:Using MRI repeated in different loading states, we established a reference for expected disc behavior with controlled loading with aging, degeneration, and by disc level. Deviations in lumbar disc mechanical behavior from the reference baseline provided by this work may provide a useful marker of disc pathology.
Background:Intervertebral disc (IVD) degeneration is associated with severe clinical symptoms including chronic back pain. Galectins are a family of carbohydrate-binding proteins, some of which can induce functional disease markers in IVD cells and other musculoskeletal tissues. Galectin-4 and -8 were shown to trigger disease-promoting activity in chondrocytes, but their effects on IVD cells have not been investigated yet. Methods:IVD specimens from 36 patients with spondylosis, spondylolisthesis, and scoliosis were assessed immunohistochemically for the presence of galectin-4 and -8. The degrees of radiological (Pfirrmann grade) and histopathological (Rutges score) degeneration of all specimens were correlated with histological galectin scores. To assess galectin functions, separate cell cultures of annulus fibrosus (AF) and nucleus pulposus (NP) (n = 21) were established. Cell cultures were treated with recombinant galectin-4, -8 (24 μg/mL), or Interleukin-1β (IL-1β) (10 ng/mL) and analyzed using RT-qPCR and In-Cell Western (ICW). Potential binding sites for galectins including sialylated N-glycans and LacdiNAc structures were determined in AF and NP cells using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results:The immunohistochemical presence of galectin-4 in IVD specimens correlated with histopathological and clinical degeneration scores of patients, whereas galectin-8 did not show significant correlations. Both galectins were detected across IVD compartments except for the endplate. In vitro, both galectins activated the nuclear factor-kB pathway and induced functional disease markers (Interleukin-8 (CXCL8) and matrix metalloproteinase-3 (MMP3) mRNA). NP cells were more responsive to galectins and IL-1β than AF cells, indicating region-specific differences in galectin sensitivity. Conclusion:This study identifies galectin-4 as a novel molecular player in the pathogenesis of IVD degeneration.
Background:Low back pain remains the leading cause of disability worldwide, with intervertebral disc degeneration representing a major biological contributor. Although cell-based therapies have shown promise in preclinical models, clinical translation has yielded modest and inconsistent outcomes. Accumulating evidence suggests that therapeutic failure reflects not only limitations in cell source or differentiation potential, but also the hostile biochemical and biomechanical microenvironment of the degenerative disc. Hypoxia, nutrient deprivation, acidity, lactate accumulation, fibrosis, senescence, inflammation, and abnormal mechanical loading collectively impair cell survival, integration, and long-term function. Method:We performed a comprehensive review of the literature using PubMed, Web of Science, and Google Scholar, with emphasis on studies published between 2020 and 2026. Evidence was critically evaluated to examine advances in cell-based therapies for IVDD, including cell sources, mechanisms of repair, biomaterial-assisted delivery systems, microenvironment-targeted strategies, translational studies, and emerging technologies that enhance regenerative efficacy. Discussion:Current evidence indicates that successful disc regeneration depends not only on selecting an appropriate therapeutic cell source but also on overcoming the biological constraints imposed by the degenerative niche. We critically compare the regenerative potential of mesenchymal stromal cells, nucleus pulposus cells, and induced pluripotent stem cell-derived therapies, highlighting their respective advantages and limitations. We further discuss how biomaterial carriers, extracellular vesicles, developmental biology-guided differentiation, genetic engineering, preconditioning approaches, and smart delivery platforms are being integrated to improve cell survival, phenotype stability, extracellular matrix restoration, and functional repair. Conclusion:Future success in intervertebral disc regeneration will require integrated therapeutic strategies that combine optimized cell sources with biomaterial-assisted delivery, microenvironment modulation, and precision bioengineering. Advancing these complementary approaches will be essential for achieving durable biological repair, restoring disc structure and function, and translating regenerative therapies into effective clinical treatments for patients with degenerative disc disease.
Background:Facet joints are highly susceptible to osteoarthritis, which can manifest in distinct patterns of cartilage degeneration across the facet joint surfaces. Understanding how cartilage structure translates into functional properties of the tissue may help to identify regions that are, from a biomechanical perspective, at higher risk for degenerative changes. Therefore, this in vitro study aimed to determine structure-function relationships based on spatially assessed surface properties of intact facet joint cartilage. Methods:Biomechanical properties were assessed by spatial stress-relaxation tests, which were performed at 12 measurement points on the cartilage surfaces of six inferior and six superior ovine facets, respectively. Cartilage thickness was determined at corresponding locations by the needle penetration method. Spatial histological analyses were performed to assess collagen and glycosaminoglycan contents, quantified from Picrosirius-red- and Safranin-O-stained sections, respectively. Differences between inferior and superior facets were analyzed using linear-mixed models; structure-function relationships were analyzed using Spearman's correlation. Results:Cartilage thickness and glycosaminoglycan coverage were significantly higher at superior facets (p < 0.05). Biomechanical properties did not significantly differ between inferior and superior facets (p ≥ 0.05). The relaxation behavior indicated a significant (p < 0.05) positive correlation with cartilage thickness at inferior facets (ρ = 0.606) and with glycosaminoglycan coverage at superior facets (ρ = 0.597). Conclusion:The biomechanical behavior of intact ovine facet cartilage was associated with its structure and the assessed properties indicated spatial variation across the facet joint surface. Overall, this study highlights the importance of topographic characterization of human facet cartilage to better understand facet osteoarthritis.
Background:The vertebral bony endplate (BEP) plays a role in regulating both mechanical load transfer and nutrient transport to the intervertebral disc, functions strongly influenced by its microstructural porosity. Variations in porosity impact bone strength, elasticity, and solute diffusion, affecting its overall mechanical competence. Methods:A semi-automated modeling workflow was established to quantify pore geometry and connectivity of the BEP and relate them to zone-specific mechanical and transport properties using relationships previously established in the literature. Six to eight BEPs from four bovine subjects were imaged using micro-computed tomography. The central zone and two peripheral zones of each BEP were segmented, and their microstructural properties, including tortuosity, porosity, and pore radii, were quantified using the pipeline to assess BEP heterogeneity. These metrics were then used to infer the BEP's zone-dependent density, Young's modulus, compressive strength, and shear modulus. Results:The BEPs showed spatial, intra-subject, and inter-subject morphological variability, which affected their predicted mechanical and transport properties. These findings highlight the limitations of purely idealized BEP representations in silico simulations and support the incorporation of uncertainty modeling strategies that account for physiologically relevant variations in the BEP. Conclusion:This semi-automated modeling approach represents a tangible step toward more realistic in silico simulations of vertebral endplate function.
ABSTRACT Background T2 relaxation time is a widely used quantitative MRI measure of intervertebral disc degeneration, correlated with water and biochemical composition. T2 time is dependent on many factors, including scan parameters, signal decay model, and region(s) of interest, such that quantification of T2 time repeatability is necessary for interpreting T2 study outcomes. Further, the sensitivity of T2 time to factors such as time of day and unloaded rest has not been sufficiently quantified. The objective of this study was to evaluate repeatability, as well as time of day and unloaded rest effects on lumbar disc T2 relaxation time. Methods Young asymptomatic participants underwent MRI. Part 1 assessed intra‐rater, inter‐rater, and inter‐scan Repeatability. Part 2 evaluated effects of Time of Day across four time points spanning 8 am to 5 pm, and 45 min unloaded Rest. T2 time was evaluated using a noise‐corrected exponential decay model for a circular region of interest (ROI) in the nucleus pulposus (NP) and for 5 regions across a mid‐sagittal line spanning the annulus fibrosus (AF), NP, and transition regions. Results Intra‐ and inter‐rater repeatability was good‐excellent (ICC = 0.76–0.99) across all regions. Inter‐scan repeatability was good‐excellent (ICC = 0.89–0.93) for the NP, while the AF had moderate‐poor repeatability (ICC = 0.17–0.53). The minimal detectable change (MDC) for the NP ROI was 31 ms. Time of Day and Rest did not significantly affect NP T2 time. Across regions, all measured changes for Time of Day and Rest were less than corresponding MDCs. Conclusions T2 time variability is primarily driven by acquisition factors, not rater subjectivity. Time of Day and Rest T2 time changes did not exceed within‐subject variability (by MDC) and therefore are not critical considerations for some study designs. The reported MDCs provide practical thresholds for interpreting individual T2 time differences.
ABSTRACT Background Several techniques have been developed to facilitate safe and accurate thoracic pedicle screw placement. However, their impact on screw anchorage has not been systematically evaluated. This study compared thoracic pedicle screw anchorage following placement using the Modified Slide, Slide, Funnel, and Conventional techniques under cyclic loading. Study Design Cadaveric biomechanical study. Methods Forty‐five fresh‐frozen human thoracic vertebrae (T4–T11) were allocated to three experimental groups (n = 15 each). For standardized paired comparisons, one randomly selected pedicle of each vertebra was instrumented using the Modified Slide technique, developed by the authors as a refinement of the original Slide technique, and the contralateral pedicle with one of three established techniques. Screws were subjected to cyclic craniocaudal loading until loosening or a maximum load level of 750 N. Results Screws placed using the Modified Slide technique withstood 1.9‐fold and 1.5‐fold more load cycles until loosening than those placed with the Slide and Funnel techniques, respectively (both p < 0.001), but only 0.9‐fold that of screws inserted with the Conventional technique (p = 0.008). Conclusions The Modified Slide technique preserves the advantage of the Funnel and original Slide techniques by allowing direct visualization of the pedicle entry point for accurate screw placement, yet substantially enhances thoracic pedicle screw anchorage compared with those techniques. Although anchorage was lower than that of the Conventional technique, screws placed using the Modified Slide technique still withstood loads substantially exceeding those reported to occur during daily activities.
ABSTRACT Background Intervertebral disc degeneration (IDD) is frequently associated with chronic low back pain (LBP), which contributes significantly to disability, psychological distress, and reduced work capacity. Mesenchymal stromal cell (MSC)‐based treatments may offer a promising, less invasive alternative to conventional treatments for IDD. The MSC secretome has shown regenerative potential through paracrine and anti‐inflammatory mechanisms. In this study, we investigated the effects of the secretome isolated from interleukin‐1β (IL‐1β)‐preconditioned bone marrow‐derived MSCs (BM‐MSCs) on human nucleus pulposus cells (hNPCs) adopting a 3D in vitro culture model. Methods The secretome (BM‐MSCsec) was collected from BM‐MSCs preconditioned with 10 ng/mL IL‐1β. hNPCs were isolated, expanded, encapsulated in alginate beads, and stimulated with IL‐1β to mimic a pro‐inflammatory environment. These cells were then treated with either standard culture media (control group), IL‐1β alone, BM‐MSCsec, or IL‐1β + BM‐MSCsec. We evaluated cell proliferation and viability via flow cytometry, nitrite and reactive oxygen species (ROS) levels using the H2DCFDA assay, glycosaminoglycan (GAG) content with the 1,9‐dimethylmethylene blue assay, gene expression of extracellular matrix (ECM) components and inflammatory markers via qPCR, and cell senescence through Western blot and β‐galactosidase staining. Results IL‐1β stimulation increased hNPC proliferation, nitrite release, ROS production, catabolic and inflammatory gene expression, and cell senescence. Treatment with BM‐MSCsec attenuated these effects, restoring proliferation to baseline levels, significantly reducing ROS and nitrite accumulation. BM‐MSCsec also upregulated anabolic genes (ACAN, COL2A1, SOX9, TIMP‐1/3), enhanced GAG production, and downregulated IL‐1β, IL‐6, IL‐8, NOS2, MMP‐1, and MMP‐13 expression. Furthermore, senescence was markedly reduced in BM‐MSCsec–treated hNPCs, with decreased β‐galactosidase activity and lower p16 and p21 expression. Conclusions Our findings support the potential of BM‐MSCsec as a cell‐free therapeutic strategy for IDD. The IL‐1β‐preconditioned secretome reduced hNPC death and senescence, mitigated inflammation and oxidative stress, and promoted ECM preservation, highlighting its potential to counteract key processes driving IDD.
ABSTRACT Introduction Intervertebral disc (IVD) degeneration remains the leading cause of low back pain worldwide. Regenerative therapies focused on restoring extracellular matrix (ECM) composition and disc height often overlook the IVD microenvironment, which remains to be fully characterized. This study first aims to profile the microenvironment of human nucleus pulposus (NP) tissue across degeneration grades from discectomy procedures, quantifying glucose, oxygen, pH, lactate, osmolarity, and 13 cytokines (TNF, IL‐1β, IL‐6, MMP‐3, β‐NGF, BNDF, IL‐10, TIMP‐1, ‐2, ‐3, FGF, and ADAMTS4 and 5). Profiling within the same samples enabled correlation analysis between all parameters. Second, this study investigated how clinically relevant microenvironmental conditions influence NP cell matrix synthesis and metabolic activity. Materials and Methods Microenvironmental profiling: NP tissue was obtained via informed consent from patients undergoing discectomy. pH was measured using a fiber optic microsensor. Oxygen was quantified using Image‐iT green hypoxia reagent. Glucose and lactate were quantified via colorimetric assays, and osmolarity was measured using a vapor pressure osmometer. Cytokines were analyzed by multiplex and enzyme‐linked immunosorbent assay (ELISA). Cellular response: NP cells were formed into microtissues and primed with TGF‐β3 for 7 days, followed by 14 days of clinically relevant microenvironmental insult with different combinations of glucose and pH or cytokine exposure and pH. Cell viability, DNA, GAG, collagen, and metabolic rates were assessed. Results and Discussion Across a broad donor cohort, microenvironmental parameters, cytokine concentrations, and ECM were maintained with increasing degeneration grades, despite notable donor variability. NP microtissues demonstrated resilience across clinically relevant ranges of glucose, pH, and cytokine exposure. This study establishes experimentally defined microenvironmental ranges that are representative of the human NP microenvironment and supported by donor‐specific in silico modeling. It further demonstrates that human NP cells within a native matrix are not highly sensitive to clinically relevant changes in microenvironmental conditions, an important consideration for cell‐based regenerative strategies.
ABSTRACT Background Cervical spondylotic myelopathy (CSM) is common in older adults. Some patients may experience incomplete neurological recovery after surgery, or even deterioration. Accurate prognosis is essential for patients, yet current tools use subjective scores and fail to detect early spinal cord microstructural changes. Methods CSM patients undergoing preoperative cervical MRI and diffusion tensor imaging (DTI) scans between 2024 and 2025 at a single center were included in this retrospective study. Data were retrieved from medical records, and the determination of whether patients achieved minimal clinically important difference (MCID) was based on the change in modified Japanese Orthopaedic Association (mJOA) scores. Three supervised learning classification models, namely extreme gradient boosting (XGB), logistic regression (LR), and support vector machine (SVM), were constructed based on DTI and clinical risk factors. The performance of these models was evaluated using the area under the receiver operating characteristic curve (AUC) and precision‐recall curve (AP), and decision curve analysis (DCA). The contribution of each feature to model prediction was visualized by SHapley Additive exPlanations (SHAP). Results The training set included 163 patients (mean age: 54.43 ± 10.27 years; 57 males), whereas the testing set included 71 patients (mean age: 54.86 ± 12.25 years; 23 males). The AUCs for XGB, LR, and SVM models in the training set were 0.940, 0.791, and 0.908 respectively (p < 0.05). The XGB model showed the best performance in the training set (AUC = 0.940, AP = 0.948), and the results in the testing set demonstrated moderate discriminative ability with good precision (AUC = 0.754; 95% CI, 0.643–0.857, AP = 0.851; 95% CI, 0.742–0.937). DCA showed that the clinical utility of the XGB model was relatively high. Conclusion An explainable XGB model based on DTI and clinical risk factors provides a foundation for preoperative risk stratification of MCID achievement in postoperative CSM.
ABSTRACT Objectives The aim of this investigation was to explore the association between disk degeneration, quantified by Pfirrmann grades and T1rho as a marker of hydration, and bone remodeling in the vertebral endplate quantified by Na[18F]F uptake on PET. Methods Subjects for this exploratory, post hoc analysis were selected from a prospective observational study on low back pain. Subjects received simultaneous Na[18F]F‐PET and spinal MRI (including T1rho mapping) in a hybrid scanner system. Tracer uptake (SUVmax) was quantified per endplate, and quantitative disk metrics were measured for annulus fibrosus and nucleus pulposus separately. Disk degeneration (Pfirrman grade) and endplate lesions (Modic changes) were assessed by a radiologist. Linear mixed models were used to investigate the association between quantitative disk and metabolic endplate metrics, adjusting for age, sex, body mass index, as well as Pfirrmann grade and Modic changes. Results Eighty‐six endplates from 9 patients (6 women) with median age 58 years (IQR: 53–72) were included. We found a positive association between annular T1rho and endplate Na[18F]F uptake (β = 0.088; 95% CI 0.018–0.159). The association was amplified by the presence of Modic changes (interaction p = 0.001). Conclusion Our findings indicate that bone remodeling of vertebral endplates is not associated with disk dehydration, and thus more likely a result of biological disk‐endplate crosstalk than a sign of increased mechanical load.
ABSTRACT Background Lumbar spinal stenosis is a prevalent and debilitating diagnosis, which in severe cases requires surgical treatment to relieve nerve root pressure. Often, treatment plans are based in part on subjective, qualitative, and limited MRI assessment. Statistical shape models (SSMs) have the potential to improve treatment indications by uncovering morphological features that work synergistically but are difficult to assess independently or directly quantify. This study examined whether 2D SSM using standard clinically relevant MRIs can differentiate between severe and normal stenosis patients in a population with low back pain. Methods A total of 62 patients were analyzed from an open‐access Lumbar Spine MRI dataset, with variable parameters, and classified as severe or normal stenosis (at L45). Intervertebral disc (IVD) and posterior element (PE) edges were extracted using the SegNet algorithm, then aligned via generalized Procrustes analysis. Aligned shapes were used for principal component analysis and principal components (PCs) were evaluated for IVD and PE independently and together. To observe if SSMs improved from anatomical measurements, facet angles, spinous process length, IVD, and thecal sac diameters were manually extracted. ANOVA and ROC analysis was run to determine the measurements' ability to discriminate between groups. Results PC1 explained 38% and 32% of the IVD and combined (IVD & PE) shape variances and had a clear difference between the severe and normal stenosis groups (p < 0.01) with moderate to strong discriminatory power (AUC = 0.89, 0.83). In comparison to anatomical measurements, the combined SSM's ability to distinguish between groups was comparable to the thecal sac diameter (AUC = 0.84) and exceeded all other traditional anatomical measures. Conclusions SSMs were able to distinguish between the severe and normal stenosis groups, specifically PC1 for both IVD and combined SSMs. Hence, this study demonstrates that SSMs could be a quantitative tool to improve stenosis diagnosis and treatment planning using clinical 2D MRIs.
