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Open research questions in Spine and Intervertebral Disc Pathology

62 unresolved questions extracted from the limitations and future-work sections of 490 Spine and Intervertebral Disc Pathology papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • 12 The longitudinal view of the anatomy provided by the sagittal method may have ensured a better placement of the steroid mixture compared to the axial method, which is limited by the facet joint and iliac crest.

    Comparison of efficacy, accuracy, and safety between axial and sagittal approaches of ultrasound guided transforaminal epidural injection for lumbar radiculopathy: A randomized controlled trial. · 2026 · DOI

  • Several limitations of this study should be acknowledged. Third, postoperative changes in sagittal alignment were not evaluated, and dynamic biomechanical alterations during functional activities could not be assessed. Therefore, prospective, multicenter studies with larger sample sizes and comprehensive biomechanical assessments are warranted to further validate and refine our findings.

    Risk factors for recurrent lumbar disc herniation after percutaneous endoscopic lumbar discectomy: the role of spinopelvic parameters and facet joint degeneration · 2026 · DOI

  • The important limitations of the current evidence, including its exclusively retrospective design, small sample sizes predominantly from East Asian popula- tions, heterogeneous measurement protocols, and the unresolved influence of CT acquisition variability on proposed HU thresholds, must be addressed before this approach can be incorporated into operative planning guidelines [5].

    CT-derived hounsfield unit mapping for pedicle screw planning in degenerative lumbar disease: a narrative review · 2026 · DOI

  • The following research priorities can be elucidated from the current evidence base. Prospective validation of trajectory HU thresholds in multi-center cohorts with standardized CT acquisition protocols and pre-spec- Table 2.

    CT-derived hounsfield unit mapping for pedicle screw planning in degenerative lumbar disease: a narrative review · 2026 · DOI

  • 99mTc-MDP SPECT/CT demonstrates substantial diag- nostic utility in identifying pain generators in patients with FBSS following SSS, particularly when conven- tional imaging is inconclusive.

    Impact of 99mTc-methylene diphosphonate single photon emission computed tomography/computed tomography on management and clinical outcomes in patients with failed back surgery syndrome · 2026 · DOI

  • Despite this interesting result, there are insufficient data to sup- port replacing the current clinical routine with 18F-NaF PET/CT.

    Impact of 99mTc-methylene diphosphonate single photon emission computed tomography/computed tomography on management and clinical outcomes in patients with failed back surgery syndrome · 2026 · DOI

  • , stand- ardized uptake values), and comparative evaluations with newer modalities such as advanced MRI tech- niques and 18F-NaF PET/CT are warranted.

    Impact of 99mTc-methylene diphosphonate single photon emission computed tomography/computed tomography on management and clinical outcomes in patients with failed back surgery syndrome · 2026 · DOI

  • Although DML testing has been introduced to detect L5/S foraminal-extraforaminal involvement, its value in guiding selective decompression and outcomes in cases of structural-functional discordance remains unclear.

    Preoperative Distal Motor Latency Testing and Long-Term Outcomes in Combined Lumbar Spinal Stenosis · 2026 · DOI

  • Future multicenter prospective randomized controlled trials incor- porating quantitative MRI parameters, annular repair status, inflammatory factor profiles, and patient-reported outcomes are warranted to better define the optimal indications for DPAE, iden- tify the patient populations most likely to benefit, and clarify its potential long-term structural protective effects.

    Real-world 24-month pain outcomes of disk percutaneous ablation and extraction versus Disc-FX nucleoplasty for lumbar discogenic pain and contained lumbar disk herniation: a single-center retrospective cohort study · 2026 · DOI

  • These findings support further investigation into muscle‑focused assessment and rehabilitation strategies as complementary components of CLBP management, rather than as replacements for existing diagnostic or therapeutic paradigms.

    Re-examining the Disc-Centric Interpretation of Chronic Low Back Pain: A Narrative Review · 2026 · DOI

  • the comparability of from modern literature injuries, limiting their in Fifth, thematic mapping and keyword-based analyses rely on author-provided terminology and indexing practices, which can lead to vary widely across overrepresentation or underrepresentation of certain themes depending on how consistently authors described procedures, complications, or anatomical findings. Fourth, underreported and that clinical experience accumulated in one institution or country rarely reaches the broader surgical community. for more robust data aggregation, adopting postoperative registries, for frameworks Although the present study confirms that ACMS scholarship remains sparse and dispersed, it provides a foundational map of existing knowledge and identifies the structural gaps that must be addressed.

    Bibliometric and network analysis of acute conus medullaris syndrome and conus-related complications after lumbar spine procedures · 2026 · DOI

  • There is insufficient justification for early MRI (within the first 4 weeks) unless there are signs of cauda equina syndrome, or epidural glucocorticoid injection or urgent surgical treatment is planned.

    Discogenic lumbosacral radiculopathy. Recommendations of the Russian Association for the Study of Pain, the Russian Society of Neurologists, the Russian Association of Neurosurgeons, the Interventional Pain Management Association, and the All-Russian Public Organisation for the Promotion of Rehabilitation 'Union of Rehabilitators of Russia' · 2026 · DOI

  • Background Superior cluneal nerve (SCN) entrapment is an underrecognized cause of low back and buttock pain, often mimicking sacroiliac joint or lumbar spine pathology.

    Superior Cluneal Nerve Radiofrequency Ablation for Chronic Low Back and Buttock Pain: A Technical Description and Case Series of Three Patients · 2026 · DOI

  • Despite these procedural challenges, no standardized grading system currently exists to objectively quantify anatomical complexity or predict technical difficulty during L5 supraneural TFESI.

    A Novel Scoring System for Predicting Procedural Difficulty in Supraneural <scp>L5 TFESI</scp> : The <scp>L5 TFESI</scp> Difficulty Score ( <scp>LTDS</scp> ) · 2026 · DOI

  • The systematic review is based primarily on single-case reports, reflecting the rarity of LPIS. The anthropometric analysis was performed on a limited number of CT scans and does not comprehensively account for individual ana- tomical variations or tumor size. Furthermore, the geomet- ric analysis was performed on normal anatomy and does not account for tumor-induced tissue displacement or for dynamic intraoperative factors such as tissue mobility and surgical retractors. A geometric advantage in working dis- tance or instrument freedom does not, by itself, translate 1 3European Spine Journal into a reduction in surgical risk. For deeply situated lesions or tumors with complex vascular relationships, the postero- lateral corridor may be unsuitable, and anterior or lateral approaches may remain safer. These anthropometric data should therefore be regarded as supplementary anatomical reference rather than as primary evidence for selecting a specific surgical approach in any individual patient. Funding This study received no external funding. Data availability No datasets were generated or analysed during the current study.

    Posterolateral approach for lumbar plexus intra-psoas schwannomas: systematic review and comparative anthropometric analysis of surgical corridors with an illustrative case · 2026 · DOI

  • This study has several limitations. First, the analysis was based on a relatively small sample from a parent randomized trial designed for treatment comparison, not for prediction modeling, so overfitting and predictor instability cannot be excluded. Variable selection was guided by clinical rationale and the EPV principle, using stepwise regression to reduce model complexity; however, some optimism bias may remain, and the model should be considered hypothesis-generating, requiring validation in larger, multicenter cohorts. Second, only internal bootstrap validation was performed, and no external cohort was available, limiting generalizability.

    Development and internal validation of a nomogram for predicting short-term functional improvement after pharmacological treatment in severe symptomatic lumbar disk herniation · 2026 · DOI

  • improve To address these limitations, future research should adopt multicenter recruitment strategies, including community and private hospitals, generalizability to across healthcare settings. Longer-term follow-up over 12–24 months is needed to determine whether psychological and satisfaction improvements are sustained or depressive symptoms re-emerge. Incorporating objective assessments of functional recovery, such as performance-based mobility tests or radiological markers, alongside self-reported measures may reduce subjective bias. In addition, integrating routine psychological screening and timely mental-health Journal of Musculoskeletal Surgery and Research • Article in Press | 7 Alzakri, et al.: Depression after lumbar stenosis surgery interventions into perioperative care pathways could improve recognition and management of persistent depressive symptoms, ultimately enhancing patient satisfaction after LSS surgery. CONCLUSION Surgical treatment of LSS in our cohort resulted in significant improvements in pain, physical function, and depressive symptoms at 6 months postoperatively. These psychological benefits were closely tied to higher patient satisfaction, reinforcing that perceived recovery extends beyond objective clinical improvement. However, persistent post-operative depression remained a major determinant of dissatisfaction, emphasizing that mental health optimization is crucial for achieving successful patient-centered outcomes. Integrating culturally sensitive psychological assessment and support into perioperative spine care may therefore further enhance patient satisfaction and recovery in Saudi Arabia. Acknowledgments: We thank all the participants in our study, without whom this research would not be possible. Author contributions: AA: Conceived and designed the study, conducted research, provided research materials, and collected and organized data; HA: Analyzed and interpreted the data; MA wrote the initial draft of the article; SA: Contributed to data collection and manuscript revision; FA: Provided methodological support and assisted in data interpretation; SFA: Critically reviewed the manuscript and provided logistical support. All authors have critically reviewed and approved the final draft and are responsible for the manuscript’s content and similarity index. Ethical approval: The research/study approved by the Institutional Review Board at King Saud University, number E-25-9738, dated May 11, 2025. Declaration of patient consent: The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given consent for clinical information to be reported in the journal. The patient understands that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

    Depression changes/persistence and patient satisfaction after lumbar spinal stenosis surgery: A prospective cohort study · 2026 · DOI

  • Funding in Existing evidence suggests that the roles of miRNAs in IDD are not rigidly manifested as protective or pathogenic, but are more likely dependent on the dynamic molecular regulatory environment in which they reside. The functional discrepancies reported by different studies may reflect variations the molecular environment of the disc across different stages of degeneration or under varying mechanical and inflammatory conditions. Although there is currently a lack of longitudinal evidence to directly validate the stage-specific functional remodeling of miRNAs, re-examining these research findings from a context-dependent perspective may help elucidate the seemingly contradictory observations in previous literature, thereby providing a theoretical framework for the rational design of miRNA-targeted therapeutic strategies. The “context dependence” this review currently remains a perspective rather than a verified theory. For it to yield genuine clinical guiding value, researchers need to address a specific and challenging question: Does the effective target gene profile of the same miRNA genuinely undergo reproducible, systemic remodeling at different time points within the same degeneration model? Until this question is answered affirmatively, therapeutic designs based on “stage matching” remain conjectural (Cazzanelli and Wuertz-Kozak, 2020; Chen et al., 2023). framework proposed in The author(s) declared that financial support was received for this work and/or its publication. This study was supported by a hospital research project (Grant No. WTFY202302).

    Context-dependent miRNA regulation in intervertebral disc degeneration: an IDD-focused dynamic network framework for stage-specific therapeutics · 2026 · DOI

  • Methodological innovations needed. The avascular nature of disc tissue and limited cell yields necessitate low‑input and single‑cell epigenomic technologies. Integrating single‑cell multi‑omics, spatial transcriptomics and long‑read epigenomics will enable high‑resolution mapping of chromatin states while preserving zonal and cellular context. Human IVDD is defined by slow, progressive epigenetic drift rather than abrupt molec‑ ular change. Longitudinal sampling strategies, particularly in aging animal models, are essential to distinguish stochastic drift from pathological transitions and to identify early epigenetic states that predispose discs to failure. Establishing standardized, disc‑specific epigenetic reference maps across age, degeneration stage and disc region will provide a founda‑ tional framework for interpreting disease‑associated changes. Such atlases are critical for cross‑study comparability and for anchoring artificial intelligence (AI)‑driven analyses in biologically meaningful ground truth. Challenges in therapeutic delivery remain stubborn. The NP tissue presents formidable barriers, creating a dilemma between achieving tissue penetration and maintaining thera‑ peutic retention. The avascular nature and dense ECM make it exceptionally challenging for systemically administered drugs to reach target cells, necessitating local intradiscal injection as the clinically relevant delivery approach (161). However, direct injection suffers from rapid diffusion outside the injec‑ tion site, resulting in short‑lived benefits while potentially causing systemic toxicity (162). The high negative fixed charge density of the NP, driven by aggrecan glycosaminoglycans, can be exploited to enhance intra‑NP residence time through positively charged delivery vehicles that utilize long‑range electrostatic interactions (163). Additionally, degenerative disc tissues develop fibrotic barriers that further impede drug penetration, further compli‑ cating therapeutic delivery (164). Advanced nanocarrier systems have emerged as promising solutions to overcome these dual challenges. Injectable hydrogel gene delivery systems incorporating functionalized nanoparticles enable sustained, on‑demand release of therapeutic agents directly into the NP, often utilizing MMP‑responsive mechanisms (165). Tannic acid‑based nanoparticles provide both antioxidant and anti‑inflammatory effects while serving as effective gene delivery vectors (166). Multiple engineering strategies can enhance nanocarrier performance. Stimuli‑responsive nanoparticles offer precise targeting and controlled thera‑ peutic release, improving drug localization and enabling sustained delivery (167).

    Epigenetic research methods and animal models for intervertebral disc degeneration (Review) · 2026 · DOI

  • Conclusions circRNAs, sequencing; immunoprecipitation circular RNAs; COL2A1, type II collagen; DNMTs, DNA methyltransferases; ECM, extracellular matrix; ERN, epigenetic regulatory network; GAGs, glycosaminoglycans; HATs, histone acetyltransferases; HDACs, histone deacetylases; IVD, intervertebral disc; IVDD, intervertebral disc degeneration; LBP, low back pain; lncRNAs, long non‑coding RNAs; miRNAs, microRNAs; MMPs, matrix metalloproteinases; MNase‑seq, micrococcal nuclease sequencing; MSP, methylation‑specific PCR; mtDNA, mitochondrial DNA; m6A, N6‑methyladenosine; ncRNA, non‑coding RNA; NP, nucleus pulposus; NPCs, nucleus pulposus cells; PPARγ, peroxisome proliferator‑activated receptor γ; PTM, post‑translational modification; ROS, reactive oxygen species; TETs, ten‑eleven translocation enzymes; WGBS, whole‑genome bisulfite sequencing; 3'UTR, 3' untranslated region; 5‑Aza, 5‑azacytidine; 5‑hmC, 5‑hydroxymethylcytosine; 5‑mC, 5‑methylcytosine Key words: epigenetic regulations, intervertebral disc degeneration, DNA methylation, histone modifications, non‑coding RNAs, animal models in epigenetics CUI et al: TOOLKIT FOR INTERVERTEBRAL DISC DEGENERATION EPIGENETICS…

    Epigenetic research methods and animal models for intervertebral disc degeneration (Review) · 2026 · DOI

  • While our data were collected from 2 ASCs with surgeries performed by 4 different spine surgeons, which helped minimize potential variability in surgical techniques and the use of biomechanical devices, the study is not without limitations. One limitation is the relatively small sample size (n = 33), which may limit the generalizability of the findings and the statistical power to draw definitive conclusions. A larger study involving a more diverse group of patients and surgeons would help provide more robust data and support the broader applicability of the findings. However, this type of study may not be feasible due to the decreased usability of outpatient surgical centers for these cases in all environments. Furthermore, the safety outcomes reported in this study should be interpreted within the context of the surgical expertise, patient selection protocols, and resources available at the ASCs included in this analysis and may not be generalizable to all outpatient surgical environments.

    Intraoperative and Postoperative Safety of Outpatient Anterior Lumbar Spine Surgery: A Multicenter Experience · 2026 · DOI

  • Future research should focus on standardizing tool selection criteria, conducting high- quality validation on the measurement properties of exist- ing instruments, and developing an AI-powered electronic PROM toolkit to promote patient-centered care.

    Patient-reported outcome measures in lumbar disc herniation: a scoping review · 2026 · DOI

  • and three affinity capture, often remains constrained by The clinical translation of MSC- and Exo-based therapies for interrelated barriers: DDD manufacturing standardization, regulatory approval, and cost (Jayaraman et al., 2021; Strecanska et al., 2025). Product standardization remains a central obstacle. Variability in donor characteristics, tissue source, MSC expansion protocols, culture conditions, and Exo isolation methods can substantially alter product quality and therapeutic performance. Current Exo including ultracentrifugation, size-based isolation approaches, filtration, generate marked heterogeneity in vesicle yield, purity, and cargo composition. Likewise, differences in MSC procurement and expansion can affect cell identity, viability, and functional stability. GMPcompliant manufacturing is therefore foundational rather than optional. For MSC-based products, this requires standardized donor screening, master and working cell bank systems, and closed, automated expansion platforms that preserve critical product attributes during scale-up. At the current stage, one of the most realistic translational routes is to prioritize banked, allogeneic, off-the-shelf MSC products, because such platforms are more compatible with reproducible batch manufacturing and large-scale distribution than patient-specific autologous approaches. For Exo-based products, translation will depend on integrated and scalable upstream–downstream workflows that combine high-yield bioreactor culture with standardized purification suitable for largebatch production, storage, and release testing.

    Mesenchymal stem cell and exosome-based therapies for degenerative disc disease: from mechanisms to clinical translation · 2026 · DOI

  • Aberrant mechanical loading triggers intervertebral disc degeneration through pyroptosis and nerve ingrowth, but quantitative biomechanical thresholds that initiate pyroptotic cascades in different disc regions and the metabolic consequences of sustained pyroptosis in nucleus pulposus cells require characterization.

    Metabolic reprogramming in intervertebral disc degeneration: mechanisms and therapeutic opportunities · 2026 · DOI

  • HIF1A upregulates autophagy to alleviate compression-induced apoptosis in nucleus pulposus-derived stem cells, but the mechanistic crosstalk between HIF1A-mediated metabolic reprogramming (glycolysis vs. oxidative phosphorylation) and autophagy flux modulation under sustained mechanical loading has not been elucidated.

    Metabolic reprogramming in intervertebral disc degeneration: mechanisms and therapeutic opportunities · 2026 · DOI

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62 open questions have been extracted from the limitations and future-work passages of 490 Spine and Intervertebral Disc Pathology papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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