Journal of Orthopaedic Research - Spine®

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JOR Spine is a fully open-access journal from @orssociety.bsky.social, dedicated to publishing high-quality spine research. https://onlinelibrary.wiley.com/journal/25721143?journalRedirectCheck=true

Screenshots of the custom app used to capture EMA.
Graphical depiction of the proposed pre-operative planning workflow.
Bone homeostasis and osteoporosis-related challenges in spinal fusion in the vertebrae. This figure illustrates the key biological & mechanical challenges affecting spinal fusion in elderly patients. In normal vertebrae, MSCs within the bone marrow differentiate into osteoblasts, which mature into osteocytes and maintain bone formation. Concurrently, hematopoietic stem cells (HSCs) differentiate into OCs, which mediate bone resorption. Under normal vascular conditions, bone formation and resorption remain balanced. In aged vertebrae, MSCs exhibit impaired osteogenic differentiation, coupled with reduced vascular supply, leading to decreased bone formation. Meanwhile, osteoblasts and osteocytes secrete increased levels of RANKL (receptor activator of nuclear factor kappa-B ligand), disrupting the OPG (osteoprotegerin)/RANKL balance and excessively activating OCs, resulting in accelerated bone resorption. Osteoporosis and degenerative disc changes contribute to fragility in the elderly.
Flowchart of the literature search.
Multiple omics in intervertebral disc (IVD) regeneration research—overview of the five main omics disciplines, genomics, epigenomics, transcriptomics, proteomics, and metabolomics, and key factors within each category that influence IVD health, IVD degeneration (IDD), and potential mechanisms for regeneration.
HPSEC profiles of CS and condoliase digestion products. (A) HPSEC profiles of undigested CS derived from shark and the digestion products of CS. One mL of CSC (1 mg/mL) was digested overnight with condoliase (0.25 U) at pH 8.0 and 37°C. (B) HPSEC profiles of extract solution from porcine nucleus pulposus and the digestion products. One mL of extract solution from porcine nucleus pulposus was digested overnight with condoliase (2 U) at pH 8.0 and 37°C.
(A) The disc height index (%DHI) values of different treatment groups at 6 weeks after puncture injury (6 W) and 4 weeks after intradiscal administration of proposed agents (10 W). (B) Radiographs and MR images of rat caudal discs at 4 weeks after intradiscal administration of proposed treatment agents. Intact: disc without puncture injury and treatment. (Error bars represent standard error).
Design of the mHealth system.
Immunohistochemical results of rat IVDs. (a) From left to right: Aggrecan expression in IVD, Aggrecan expression in nucleus pulposus, SOD2 expression in IVD, and SOD2 expression in nucleus pulposus. From top to bottom: 31G needle group, vehicle group, 0.5 μg AGEs group, 1 μg AGEs group, 2 μg AGEs group, 4 μg AGEs group, and non-ovariectomy group. (b) Statistical results of Aggrecan expression in the nucleus pulposus of the coccygeal disc of rats. (c) Statistical results of SOD2 expression in the nucleus pulposus of the coccygeal disc of rats. Those labeled with the same letter indicate no statistical difference between groups, and those with different letters indicate a statistical difference between groups (p < 0.05).
UNET++ appropriately segments disc tissues with high performance. (A) Mean (averaged across tissues) intersection over union (mIOU) and tissue frequency weighted mean intersection over union. Each dot is one histology section from one rat (n = 11), mean and standard deviation are also plotted. (B) Mean intersection over union for each tissue. Each dot is one histology section from one rat (n = 11), mean and standard deviation are also plotted. (C) Representative H&E images of rat representing healthy (Ci, Di, and Ei), moderate (Cii, Dii, and Eii), and severely degenerated samples (Civ, Div, and Eiv). Region of interest (ROI) shown for moderate (Ciii, Diii, and Eii) and severely degenerated samples (Cv, Dv, and Ev) where modest misclassification of the NP, AF, Endplate, and Granulation tissue occur (Noted with Arrow) (D) Representative H&E images of rat disc tissue with ground truth (GT) annotations with respective ROIs. (E) Representative H&E images of rat disc tissue with model ROIs.
Approximate range of motion (ROM) (A-C) of animal cervical and lumbar spine segments in axial rotation (A) flexion-extension, (B) lateral-bending (C) as a percentage of human lumbar ROM and axial rotation at different spinal levels for the kangaroo and humans (D).15, 97-101 References for benchmark data are: Human Lumbar,101, 102 Porcine Lumbar and Porcine Cervical,98 Ovine Lumbar and Ovine Cervical,99 Caprine Lumbar,15 Calf Lumbar.103 Relative sizes of human and kangaroo lumbar and cervical Llama and Alpaca IVDs (E). Macroscopic views of horizontally bisected kangaroo L1L2 (F), L2L3 (G) L4L5 (H), human L4L5 (I) and Llama C4C5 (J) and Alpaca C3C4 (K) IVDs. Images F-H were kindly supplied by Dr Uphar Chamoli, Director of Engineering, Kunovus Pty Ltd, School of Biomedical Engineering, University of Technology, and St. George Clinical School, University of NSW, Sydney, Australia. Images J, K reproduced from21 with permission.
Percentage of studies using selected grading systems over time from 2000 to present. Pfirrman grading (~10% in 2000 to ~80% by 2015) is consistently used more than Modified Pfirrman and T2 mapping (<20% at all timepoints until ~2025). Over time, the Pfirrmann grading system was consistently used, particularly between the early 2000s and mid-2010s, where it was used in over 50% of studies. In contrast, T2 mapping showed minimal use in early years but increased steadily over time, particularly from 2010 to onwards. This trend reflects a gradual shift toward incorporating more objective, quantitative imaging methods in DD research.
The flowchart of this study. GTEx, genotype-tissues expression project; GWAS, genome-wide association; FUSION, functional summary-based imputation; MAGMA, multi-marker Analysis of GenoMic Annotation; TWAS, transcriptome-wide association studies; UTMOST, unified test for molecular signatures.
WJ-MSC-derived EVs promoted hNPC proliferation and viability. (A) Cell content significantly increased after treatment with 10 μg/mL WJ-MSC-EVs at day 4, 10, and 14, as compared with the IL-1β control group (n = 4). Data were analyzed through two-way ANOVA with Dunnett's multiple comparisons test, where each group was compared with IL-1β. Within each timepoint, values were analyzed using unpaired t tests with a false discovery rate approach. (B) After 24 h, the WJ-MSC-EV treatment significantly reduced IL-1β-pre-treated hNPC death at 100 μg/mL at flow cytometry (n = 4). Data were analyzed through two-way ANOVA with Dunnett's multiple comparisons test, where each group was compared with IL-1β. (C) Live/Dead staining showed reduced cell death in hNPCs treated with 10 and 100 μg/mL WJ-MSC-EVs (n = 4). Magnification: 20×, scale bar: 100 μm.*p < 0.05, **p < 0.01, compared to the control group. #p < 0.05, ##p < 0.01, ###p < 0.001 compared to the IL-1β group. Abbreviations: AM, acetoxymethyle
The left most image displays the locations of inertial measurement unit (IMU) sensors on the body during in-clinic testing. Sensors were positioned at the following locations: T1/T2, T12/L1, L5/S1, and right lateral thigh and display the IMU segments. The two images to the right are still images illustrating the preparation and placement of IMUs. Top: Four IMUs are powered on and placed on a flat surface as the physical therapist applies skin adhesive to each unit (skin adhesive in white on lower right sensor). Bottom: The physical therapist palpates the L5/S1 anatomical landmark to ensure accurate placement of the sensors, while the T12/S1 sensor is already affixed on the skin over the spine.
Schematic depiction of the innervation of the degenerate IVD and associated tissues. Figure part (a) reproduced from [3], (b) modified from [35] with permission. ALL, anterior longitudinal ligament; DRG, dorsal root ganglion; PLL, posterior longitudinal ligament; and (c) schematic depiction of the dorsal root ganglion in relation to the IVD and associated spinal tissues, SC, spinal cord.
Workflow overview: PROMs were collected from workers suffering from cLBP during the first visit. Each questionnaire was preprocessed separately for features encoding, reduction, and normalization. Two slightly different preprocessing modalities were employed before clustering and profiling. The encoded questionnaire was ultimately employed for patient profiling according to the predicted cluster labels. Occupational queries were used for profiling only. CLBP, chronic low back pain; PCA, principal component analysis; PHQ-2, Patient Health Questionnaire 2; PROM, patient-reported outcome measure; ODI, Oswestry Disability Index; VAS, Visual Analog Scale; WAI, Work Ability Index.
Partial correlations between the quantitative MRI and disc health measures in the (A) nucleus pulposus (NP), (B) ventral aspect of the annulus fibrosus (vAF), and (C) dorsal aspect of the annulus fibrosus (dAF) using linear models with “dog” and “disc level” as block effects. Crossed out values (×) are nonsignificant (p ≥ 0.0125 or p ≥ 0.025 with Bonferroni correction for four (A and B) or two (C) disc health measures, respectively). In the NP, the relaxation times were moderately and negatively correlated with Pfirrmann grade and histology score, and moderately and positively correlated with water content. T2 and aT2ρ were also weakly and positively correlated with GAG content. In the vAF and dAF, aT2ρ was weakly and positively correlated with Pfirrmann grade. Additionally, in the vAF, T1ρ and aT1ρ were weakly and positively correlated with water content. Additional details of these relationships are shown in Tables 4–6.
Graft microstructure represented by scanning electron micrographs. sCaP granules (A, B) isolated from sCaP/AOC graft and (C, D) embedded within the collagen matrix of sCaP/Col I graft. (E, F) mCaP granules embedded within the collagen matrix of mCaP/Col I graft.
Distribution of Pro-Inflammatory cytokines across Pain and ODI categories. Each panel shows box-and-whisker plots of cytokine levels (TNF, IL-15, Leptin, IFN-γ) across three categories of pain (in blue; mild, moderate, severe) and three categories of disability (in red; mild, moderate, severe, per the Oswestry Disability Index [ODI]). The box boundaries represent the 25th and 75th percentiles, the horizontal line within each box is the median, and the whiskers extend to the minimum and maximum values (excluding outliers). Numeric annotations (e.g., mean, median, min, max) are displayed above each group.
Dark blue bars represent main categories whereas light blue bars represent sub-categories. Treatments are presented in categories from most to least frequent.
Temporal summation: X-axis displays the mean differences in pain ratings associated with pinprick stimuli. In each of three trials, participants received a set of 10 pinpricks; participants then numerically rate the pain elicited after the initial (first) and final (10th) pinprick. The 0–10 pain rating of the first pinprick is subtracted from the 0–10 rating of the 10th pinprick, for each trial. The mean values were derived from the three applications of pinpricks, each performed over the low back (site of pain) and the palmar forearm (control site). A negative value indicates that the first pinprick is rated as more painful than the 10th pinprick. A positive value indicates that the 10th pinprick is rated as more painful than the first pinprick.
Graphic representation of vertebral height measurements. The lighter bars show the right, or convex side, height and the left, or concave side, height. The darker bars show the anterior height and the posterior height.
Classic CPG model diagrams at three different levels.
Data analysis flowchart. The data collection inputs are highlighted in the green column (left). Tantalum beads, digitized in both CT and experimentally, are used to co-register the vertebrae. Pure moment bending (simulated axial rotation shown) is performed using the spine kinetic simulator and motion is recorded via optical motion capture. Helical axes were computed throughout motion and used to derive the helical compliance vector and corresponding kinetic measures: compliance, directional compliance, deviation angle, and variability of the deviation angle. Disc and facet joint health are measured via magnetic resonance imaging.
The flowchart of this study.
In vitro effects of ultrafine-grained stainless steel implants on Staphylococcus aureus biofilms.
The figure combines ferroptosis and cuproptosis in IVDD and identifies five key targets of GSH, oxidative stress, TCA cycle, autophagy, and copper.
MRI analyses of mean modified Pfirrmann scores (A), DHI (B) and T2 relaxation times in the study groups. DHI and T2 relaxation time have been calculated as percent change compared to baseline. *p < 0.05, ****p < 0.0001 between groups. #p < 0.05, ##p < 0.01, ###p < 0.001 compared to baseline. BM-MSC = bone marrow-derived stromal cell; DHI = disc height index.
Summary of study findings concerning adipokine function in vertebral pathology, sarcopenia, degenerative disc disease and ligament ossification. (OP) = osteoporosis. (MMP) = matrix-metalloproteinases. (ADAMTs5) = a disintegrin and metalloproteinase with thrombospondin motifs 5. (mFb) = mineralized fibroblast. (Ca2+) = calcium. (Green Triangle) = positive/anti-inflammatory role. (Red Triangle) = negative/inflammatory role. (Green-Red Triangle) = Conflicting results reported in the literature regarding inflammatory/anti-inflammatory role.
Vertebrae of the bovine tail viewed ventral (left) and dorsal (center) aspects in the fully extended posture and lateral aspect (right) with locations and extents of intrinsic muscles (as reported by Young and Kenrick [35]) shaded and ranges of in vivo sensor pods indicated.
Safety and efficacy of repeated epidural HPE injections in promoting functional recovery in rats with LSS. (A) Weekly body weight measurements over a 4-week period for each group. (B) Serum CRP levels at weeks 1 and 4 for each group. (C) Serum ALT levels at weeks 1 and 4 for each group. (D) Footprint analysis at 4 weeks before the autopsy. (E–I) Quantitative analysis of stance width, stride length, step length, toe-out angle, and paw area from three consecutive imprinted footprints in each group. (J) Behavioral recovery assessed using the BBB locomotor rating scale over four weeks for each group. (K) Ladder test performance over four weeks, evaluating skilled walking and coordination for each group. (L) Von Frey test measuring mechanical allodynia over four weeks for each group. Statistical analysis was performed using one-way analysis of variance (ANOVA) complemented by Tukey's post hoc test. Significance demarcations are as follows: ###p < 0.001 and ####p < 0.0001 compared with the S
(A) Three main assumptions of Mendelian randomization. (1) relevance assumption, (2) independence assumption, (3) exclusion restriction assumption. (B) The flowchart of a MR study. (C) Two-step MR study of GM on IVDD mediated by blood metabolites. IVDD, intervertebral disc herniation; IVs, instrumental variables; IVs, instrumental variables; IVW, inverse variance weighted; LD, linkage disequilibrium; β1, influence of GM on metabolites; β2, influence of metabolites on IVDD; β3, total effect GM on IVDD.
(A) Schematic of tissue preparation for ICP-OES and LA-ICP-MS in the nucleus pulposus (NP) and annulus fibrosus (AF) regions. Measurements of sodium concentration normalized to tissue hydration via (B) ICP-OES and (C) LA-ICP-MS in NP and AF tissue after diurnal testing. Each circle is the average of the 30 ablation regions, *p < 0.05 for a t-test between time points within region and the p values from a two-way ANOVA are shown in the plot. N = 4/region/time.
Schematic of research design. (1) Longitudinal assessments included pre-op up to 12 weeks inclusive of magnetic resonance imaging (MRI), Von Frey assessments (VFA), blood draw for plasma, and fluoroscopy as indicated by the timeline. (2) Tissue was collected at 12 weeks for IVD (left) and DRG (right) assessments as indicated by colored intervertebral discs (green = dimethylmethylene blue assay, purple = picrosirius red/alcian blue, black = magnetic resonance imaging, μCT, and mechanics) and circles representing DRGs (blue = electrophysiology, red = RNASeq). Figure created using Biorender.com.
Experimental photographs representing the final deformed state of foam-implant systems using the force control (left, red) and the ASTM-based test setup (right, blue).
A) Summary flow chart of test procedure, black line shows point where specimens are frozen then thawed to continue process B) hold period and biomechanical test compressive loading, and C) treatment injection fixture set up (not to scale).
Primary characteristics in IVD research investigating the role of sex hormones. (A) Publications identified in our search stratified by year of publication. (B) Model species used in the laboratory and/or clinic in each study. (C) Distribution of biological sexes investigated in IVD research related to sex hormones.
(a) Physiological finite element model of the L1—L5 lumbar spine (b) Geometry and volume mesh of the vertebra with cortical and trabecular bone (c) FE model of the intervertebral disc with cartilaginous endplates. The intervertebral disk was modeled as consisting of a nucleus pulposus and annulus ground matrix formed by eight layers of annular fibers.
Dynamic biplane radiography data collection and processing. (A) Participants performed F/E and LB motions while (B) synchronized biplane radiographs were collected. (C) CT scans were collected and bone tissue segmented to (D) create 3D bone models. (E) Intervertebral motion was measured using a validated volumetric model-based tracking process with submillimeter accuracy that matched digitally reconstructed radiographs created from subject-specific CT-based bones to biplane radiographs, and (F) six degrees of freedom vertebral kinematics were calculated.
Diagram of the mechanism by which macrophage polarization influences IVDD by modulating the inflammatory microenvironment
(a) Schematic of the AF sample harvested (light shaded portion) from the individuals with degenerative disc disease and non-DD individuals. Sample dimension parameters labeled as: (1) Circumferential Length, (2) Disc Height/Tissue Width, (3) Radial Length, and (4) Peel Length. The blue and orange shaded faces of the sample showcase the change in orientation of the sample from (a) to (b). (b) Schematic showing the preparation of the peel test sample. The tissue strip on the left shows the Peel Length in red and the projected incision in white. The tissue is cut along the white line using a number 11 scalpel blade. The tissue strip on the right with the incision shows the annular tabs that are used to clamp the tissue for the peel test. Wp is the tissue width (disc height), Fp is the force experienced by the tissue for delamination, and Fc is the force exerted by the clamp to stretch and delaminate the tissue. Clamp force, Fc, is assumed to be equal to the peel force, Fp.
Representative Safranin O/Fast Green staining images of sagittal sections of IVDs. Bovine coccygeal IVD organ explant cultured with different loading regimes for 7 days and 6 μm sections from EDTA-decalcified and paraffin-embedded tissue. Scale bar: 2 mm.
(A) The central proposal of this work was that a treatment for disc-associated pain could be fabricated from a mixture of decellularized healthy porcine NP tissue, collagen, and genipin. This therapeutic would theoretically be tissue integrating, spontaneously fibrillogenic, cytocompatible, and biomechanically restorative, leading to pain-like behavior remission. (B) The first arm of this work entailed testing decellularized nucleus pulposus gels supplemented with 6.0 mg/mL collagen and genipin from 0 to 20 mM. Testing of these gels (dNPs) included gelation kinetics, rheology, cytotoxicity, and ex vivo capacity to restore injured disc mechanics. (C) The outcomes of the first arm determined that the optimal formulation to test in vivo was 6.0 mg/mL dNP + 6.0 mg/mL collagen +2.5 mM genipin, referred to in this manuscript as dNP+. To test this therapeutic, disc degeneration was induced in female Sprague Dawley rats and allowed to progress for 8 weeks. At 9 weeks post-injury.
TNFR1 is greater in AF than in NP and is affected by injury in NP. Sham (n = 4 AF, n = 4 NP) and injured (n = 6 AF, n = 6 NP) rat lumbar IVDs with TNFR1 (A, C) and TNFR2 (B, D) IHC with TolBlue counterstain. TNFR1 is greater in AF than in NP for Sham. TNFR1 is greater in Injury than Sham in NP. TNFR2 is lowly expressed and is not affected by IVD region or injury condition. (4-6 biological donors; *p < 0.05).
(A) Representative Alcian blue and picrosirius red (ABPR) and (B) hematoxylin and eosin (H&E) stained mid-sagittal histological sections of healthy and degenerate goat discs; scale = 5 mm. Note the presence of endplate damage and associated eruption of disc tissue into adjacent vertebrae in the severely degenerate disc (arrow). (C–G) Semi-quantitative histological grading of NP cellularity, NP matrix, AF organization, AF/NP border, and CEP structure. (H) Overall histological grade. *p < 0.05 versus healthy; N = 3–6; median and interquartile range.
Case reporting and completeness of data collection.
Diagram of the mechanism by which macrophage polarization influences IVDD by modulating the inflammatory microenvironment.
Mouse IVD images showing tissue staining and DR showing the disk height statistics. (A) Saffron O, Fast Green, and Alcian Blue staining (scale bar: 200 μm, magnification ×10); (B, C) DR and caudal vertebrae of adult and aged mice and height statistics; (D) IVD altered histological scoring statistic (*p < 0.05, ****p < 0.0001). Each point on the statistical chart represents a mouse.
Flow diagram presenting the main plan and process of the study.
Study flowchart: Overall study diagram.
Functional annotation and immune infiltration analyses. (A–C) GSEA of BID, TMTC1, and TNFAIP6 in the GSE70362 dataset. (D) Co-expression network of key genes constructed leveraging the GeneMANIA database. (E) Abundance of 28 types of immune cell infiltrates between IDD and control samples in the GSE70362 dataset, calculated applying the ssGSEA algorithm. (F) Box plot visualizing differences in immune cell infiltrates between IDD and control samples. (G) Correlation analysis of differential immune cells. (H) Heatmap showing the correlations between differential immune cells and key genes. *p < 0.05, **p < 0.01.
Increased lipotoxicity were detected in IDD
PE promotes autophagy in NP cells under stress conditions. (a, b) Representative images and quantification of LysoTracker Red in NP cells with the indicated treatments. Scale bar: 20 μm. ***p < 0.001, ****p < 0.0001. (c, d) Representative images of LC3 and p62 in NP cells with the indicated treatments. Scale bars: 10 and 20 μm. n = 5 independent biological replicates. ***p < 0.001, ****p < 0.0001. (e, f) MDC staining of the cells with the indicated treatments. Scale bars: 10 μm. n = 5 independent biological replicates.**p < 0.01, ***p < 0.001, ****p < 0.0001. (g, h) The WB results and quantitative analysis of Beclin1, CTSD, LC3, P62 and GAPDH in cells with the indicated treatments. n = 3 independent biological replicates. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (i) Representative TEM images of the samples with the indicated treatments. n = 5 independent biological replicates. Scale bar: 2 μm.
Tasks simulated in OpenSim. From left to right: Axial lift, lateral lift, flexion lift with two hands, flexion lift with one hand, and opening a window. Weight lifted is set at 10% of body weight.
Flowchart of online toxicology of nicotine-induced disc degeneration.
The Decay Variance (DeVa) workflow. (1) Patient with chronic low back pain is referred to a radiology centre for magnetic resonance imaging (MRI). (2) The patient undergoes a T2*-weighted 2D FLASH multi-echo MRI with a minimum of 6 echo times. (3) The sequence generates 6 images with different signal intensities for each intervertebral disc (IVD). (4) The DeVa software merges the 6 images into 1 in the working portal for the practitioner to trace each IVD as a region of interest (ROI). (5) The DeVa software then post-processes the image. (6) A quantitative DeVa score for each disc as well as a qualitative signal intensity DeVa map is then generated in the form of a report.
Analysis workflow. After immunohistochemical staining, the slides are scanned and analyzed using QuPath before proceeding with statistical analysis and graph creation. Prior to running the QuPath batch analysis, the system undergoes training, during which the Cell Detection parameters are defined, an object classifier is trained, and regions of interest are selected (Figure 2). Batch analysis is then performed within a QuPath project based on the pre-defined parameters established during the initial training process. During this analysis, cells within the regions of interest are detected according to the pre-set parameters and classified as either “positive cell,” “negative cell,” or “no cell.” The batch process analyzes all slides within the project and generates a folder containing text files with the results. In the subsequent step, a Python script consolidates these text files into a single Excel spreadsheet, which provides the positivity rate for each region of every slide.
Predicted mRNA profiles for cells not exposed and exposed to pro-inflammatory cytokines for five human habits: sitting, walking, hiking with 20 kg extra weight, jogging, and exposure to high vibration, and within three different nutrient (nut.) environments being optimal (pH 7.1, 5 mM glucose), critical (pH 6.95, 1.03 mM glucose), and early degenerated (pH 6.93, 0.89 mM glucose).
β-catenin and CCL2 expression was increased in Sox9 deleted disc tissues. Immunohistochemistry data (L4/5, n = 3, scale bar 100 μm in A, 25 μm in B) demonstrated that β-catenin and CCL2 protein expression was markedly increased (yellow arrows and red arrows, right panel) in disc tissues from 4-month-old Sox9cKO mice when SOX9 protein expression was not detected by administration with tamoxifen (1 mg/10 g body weight, IP, daily for 5 days) at 8 weeks of age.