Background. Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). Degenerate discs are associated with accelerated cellular senescence. Cell senescence is associated with a secretory phenotype characterised by increased production of catabolic enzymes and cytokines. However to date, the mechanism of cell senescence within disc degeneration is unclear. Senescence can be induced by increased replication or induced by stress such as reactive oxygen species or cytokines. This study investigated the association of cellular senescence with markers of DNA damage and presence of cytoplasmic DNA (which in cancer cells has been shown to be a key regulator of the secretory phenotype), to determine mechanisms of senescence in disc degeneration. Methods and Results. Immunohistochemistry for the senescence marker: p16. INK4A. was firstly utilised to screen human intervertebral discs for discs displaying at least 30% immunopostivity. These discs were then subsequently analysed for immunopostivity for DNA damage markers γH2AX and cGAS and the presence of cytoplasmic DNA. The number of immunopositive cells for p16. INK4A. positively correlated with the expression of γH2AX and cGAS. Senescent cells were also associated with the presence of cytoplasmic DNA. Conclusions. These new findings elucidated a role of cGAS and γH2AX as a link from genotoxic stress to cytokine expression, which is associated with senescent cells. The findings indicate that cellular senescence in vivo is associated with DNA damage and presence of cytoplasmic DNA. Whether this DNA damage is a result of replicative senescence or stress induced is currently being investigated in vitro. No conflicts of interest. Sources of funding: Funded by ARUK and MRC

Background. Endplate defect is an MRI trait, found to be associated with intervertebral disc degeneration. There is a lack of understanding regarding the mechanism underlying lumbar disc degeneration (LDD). This large-scale longitudinal population-based study aimed to determine the order of appearance of degenerative change in the vertebral body and intervertebral disc, the influence of endplate degeneration on LBP and whether there is a genetic influence on endplate damage. Methods. Individuals from the TwinsUK spine study having longitudinal T2-weighted lumbar MRI scans at baseline (n=996) and a decade later (n=438) were included. LDD, vertebral endplate defect expressed as a total endplate (TEP) score and Modic change (MC) were assessed using standard techniques. Mixed-effects models were used to determine the association between spine pathology features adjusted for covariates. Endplate defect heritability was estimated using variance component analysis. Results. Significant association between endplate defect, LDD, MRI features of LDD and MC was observed. Endplate defect was independently associated with severe disabling LBP episodes. An association between LDD at baseline and MC at follow-up was shown at upper lumbar levels. TEP score was heritable with estimated additive genetic component A = 55.3% (95% CI 43.0–65.4). Conclusion. Endplate defect, LDD and MC are all independent risk factors for episodes of severe and disabling LBP. Longitudinal analysis showed LDD is followed by MC. Endplate defect has significant heritability. However, whether endplate defect triggers LDD or these pathological changes occur concurrently could not be determined conclusively. Conflicts of interest: none. Sources of Funding: This work was funded by the EU FP7 project Pain_Omics

Introduction

Physical disruption of the extracellular matrix influences the mechanical and chemical environment of intervertebral disc cells. We hypothesise that this can explain degenerative changes such as focal proteoglycan loss, impaired cell-matrix binding, cell clustering, and increased activity of matrix-degrading enzymes.

This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review

Aims. In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD. Methods. An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD. Results. A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats. Conclusion. DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD. Cite this article: Bone Joint Res 2024;13(5):247–260

Background. Chronic low back pain is strongly linked to degeneration of the intervertebral disc (IVD), which currently lacks any targeted treatments. This study explores NPgel, a biomaterial combined with notochordal cells (NC), developmental precursor cells, as a potential solution. NCs, known for anti-catabolic effects on IVD cells, present a promising avenue for regenerating damaged IVD tissue. Methods. Bovine IVDs underwent enzymatic degeneration before NPgel (+/- NC) injection. Degenerated bovine IVDs were cultured under biomechanical loading for 21 days. Histology and immunohistochemistry assessed NC survival, phenotype, and matrix production. Within an in vivo sheep pilot study, NPgel (+/- NC) was injected into degenerated IVDs, blood was taken, and immune cell activation was monitored via flow cytometry over three months post-injection. Results. Within the ex vivo model, IVDs injected with NPgel (+/- NC) exhibited increased matrix expression and deposition. Viable NCs were detected post-culture, indicating survival and matrix production. In the in vivo model, NPgel injection into sheep IVDs did not significantly increase activation of immune cells compared to controls, suggesting no systemic inflammatory effects. Conclusion. NPgel, combined with NCs, shows promise for IVD regeneration. Ex vivo findings indicate NPgel supports NC survival and matrix production. Moreover, in vivo results demonstrate the absence of systemic immunogenic responses post-NPgel injection. This suggests NPgel's potential as a carrier for NCs in IVD regeneration therapy. These findings underscore NPgel's candidacy for further investigation in addressing chronic low back pain associated with IVD degeneration. Subsequent research, including long-term efficacy and safety evaluations, is imperative for clinical translation. Conflicts of interest. There are no conflicts of interest. Sources of funding. iPSpine, grant # 825925, Horizon 2020

Objectives. Understanding lumbar facet joint involvement and biomechanical changes post spinal fusion is limited. This study aimed to establish an in vitro model assessing mechanical effects of fusion on human lumbar facet joints, employing synchronized motion, pressure, and stiffness analysis. Methods and Results. Seven human lumbar spinal units (age 54 to 92, ethics 15/YH/0096) underwent fusion via a partial nucleotomy model mimicking a lateral cage approach with PMMA cement injection. Mechanical testing pre and post-fusion included measuring compressive displacement and load, local motion capture, and pressure mapping at the facet joints. pQCT imaging (82 microns isotropic) was carried out at each stage to assess the integrity of the vertebral endplates and quantify the amount of cement injected. Before fusion, relative facet joint displacement (6.5 ± 4.1 mm) at maximum load (1.1 kN) exceeded crosshead displacement (3.9 ± 1.5 mm), with loads transferred across both facet joints. After fusion, facet displacement (2.0 ± 1.2 mm) reduced compared to pre-fusion, as was the crosshead displacement (2.2 ± 0.6 mm). Post-fusion loads (71.4 ± 73.2 N) transferred were reduced compared to pre-fusion levels (194.5 ± 125.4 N). Analysis of CT images showed no endplate damage post-fusion, whilst the IVD tissue: cement volume ratio did not correlate with the post-fusion behaviour of the specimens. Conclusion. An in vitro model showed significant facet movement reduction with stand-alone interbody cage placement. This technique identifies changes in facet movement post-fusion, potentially contributing to subsequent spinal degeneration, highlighting its utility in biomechanical assessment. Conflicts of interest. None. Sources of funding. This work was funded by EPSRC, under grant EP/W015617/1

Background. Magnetic resonance imaging (MRI) algorithm identifies end stage severely degenerated disc as ‘black’, and a moderately degenerate to non-degenerated disc as ‘white’. MRI is based on signal intensity changes that identifies loss of proteoglycans, water, and general radial bulging but lacks association with microscopic features such as fissure, endplate damage, persistent inflammatory catabolism that facilitates proteoglycan loss leading to ultimate collapse of annulus with neo-innervation and vascularization, as an indicator of pain. Thus, we propose a novel machine learning based imaging tool that combines quantifiable microscopic histopathological features with macroscopic signal intensities changes for hybrid assessment of disc degeneration. Methods. 100-disc tissue were collected from patients undergoing surgeries and cadaveric controls, age range of 35–75 years. MRI Pfirrmann grades were collected in each case, and each disc specimen were processed to identify the 1) region of interest 2) analytical imaging vector 3) data assimilation, grading and scoring pattern 4) identification of machine learning algorithm 5) predictive learning parameters to form an interface between hardware and software operating system. Results. Kernel algorithm defines non-linear data in xy histogram. X,Y values are scored histological spatial variables that signifies loss of proteoglycans, blood vessels ingrowth, and occurrence of tears or fissures in the inner and outer annulus regions mapped with the dampening and graded series of signal intensity changes. Conclusion. To our knowledge this study is the first to propose a machine learning method between microscopic spatial tissue changes and macroscopic signal intensity grades in the intervertebral disc. No conflict of interest declared.  . Sources of Funding. ICMR/5/4-5/3/42/Neuro/2022-NCD-1, Dr TMA PAI SMU/ 131/ REG/ TMA PURK/ 164/2020. A part of the above study was presented as an oral paper at the International Society for the Study of Lumbar Spine (ISSLS) meeting held on 1–5. th. May 2023, Melbourne, Australia

Introduction. Degenerative cervical myelopathy (DCM) is associated with progressive neurological deterioration. Surgical decompression can halt but not reverse this progression. The Modified Japanese Orthopaedic Assessment (MJOA) tool is recommended by international guidelines to grade disease severity into mild, moderate and severe, where moderate and severe are both recommended to undergo surgical intervention. During Covid-19 Nottingham University Hospitals (NUH) NHS Trust, identified DCM patients as high risk for sustaining permanent neurological damage due to surgical delay. The Advanced Spinal Practitioner (ASP) team implemented a surveillance project to evaluate those at risk. Methods. A spreadsheet was compiled of all DCM patients known to the service. Patients were telephoned (Oct-Nov 2021) by an ASP. MJOA score was recorded and those describing progressive deterioration were reviewed by the ASP team on a spinal same day emergency assessment unit. Incident forms were completed for clinical deterioration and recorded as severe harm. Acute, progressive neurological deterioration was fast tracked for emergency surgical decompression. Results. 45 patients were telephoned, 18 (40%) had deteriorated. Of the 18, 9 underwent urgent surgical decompression, 6 still await surgery and 3 continue to be monitored. Those who had deteriorated were sent a formal apology and duty of candour letter. Conclusion. It appears that patients with a diagnosis of DCM deteriorate over time. Delays to timely surgical intervention can have a deleterious effect on patient's neurological function. Baseline assessment should be clearly documented and scoring system such as MJOA considered for effective monitoring. Safety netting for deterioration should be standard practice, and a clear pathway for emergency presentation identified. Conflicts of interest: No conflicts of interest. Sources of funding: No funding obtained

Background. We have previously reported an injectable hydrogel (NPgel), which could deliver patients own stem cells, via small bore needles, decreasing damage to the annulus fibrosus. NPgel drives differentiation to NP cells and can inhibit the degenerate niche. However, clinical success of NPgel is dependent on the capacity to inject NPgel into naturally degenerate human discs, restore mechanical function to the IVD, prevent extrusion during loading and induce regeneration. This study assessed injectability of NPgel into human IVD, influence on mechanical properties, regeneration ability in an ex vivo culture system and retention under failure testing. Methodology. Cadaveric human discs were used to calculate disc height and to determine Youngs Modulus during simulated walking pre and post injection of NPgel, extrusion testing performed. Whole human IVDs were injected with NPgel +/− human BMPCs and maintained in culture under physiological loading regime for 4 weeks. Pre and post culture MRI imaging and in line biomechanical characteristics determined. Histology and immunochemistry performed for anabolic and catabolic factors. Results. NPgel injection significantly increased disc height and Youngs modulus with no extrusion observed during failure testing. T1ρ intensity was increased during culture in those injected with NPgel +/− cells compared to non-injected discs, and biomechanical restoration. Histological analysis has demonstrated excellent tissue attachment to the injected gel, and cellular migration into acellular gel systems. With increased matrix production and decreased catabolic factor expression. Conclusion. These results provide essential proof of concept data supporting the use of NPgel as an injectable therapy for disc regeneration. Conflict of interest: C Le Maitre & C Sammon are inventors on the hydrogel discussed. Funding: This work was funded by MRC and Versus Arthritis

Introduction. Nucleus replacement surgery has the potential to be an early treatment option for chronic lower back pain. The surgery involves removal (nuclectomy) and replacement of the native degenerated nucleus with a material designed to restore the disc's physiological properties. Multiple techniques have been considered to perform a nuclectomy, however the advantages and disadvantages of each are not well understood. The aim of this study was to quantitatively compare three nuclectomy techniques: automated-shaver, rongeurs, and laser. Methods and results. Fifteen human vertebra-disc-vertebra lumbar specimens were split into three groups. Before and after nuclectomy axial mechanical tests were performed and T2-weighted 9.4T MRIs were acquired for each specimen. Using the automated-shaver and rongeur similar volumes of disc material were removed (2.51±1.10% and 2.76±1.39% of the total disc volume, respectively), whilst considerably less material was removed when using the laser (0.12±0.07%). Using the automated-shaver and rongeur significantly reduced the toe-region stiffness, while the linear region stiffness was significantly reduced only in the rongeur group. From the MRIs, more homogeneous cavities were seen in the center of the disc when using the automated shaver compared to rongeur, whilst laser ablation resulted in small, localized cavities. Conclusion. Results suggest that the current laser parameters are not suitable for removal of large volumes of material unless the technique is optimised for this application. Both rongeurs and automated-shavers can be used to remove large volumes of material but the reduced risk of collateral damage to surrounding tissues suggests that an automated-shaver may be more suitable. Conflicts of interest: No conflicts of interest. Sources of funding: Part of this work was funded by an Imperial College Research Fellowship for NN and an EPSRC DTP CASE Conversion Studentship for TR (EP/R513052/1)

Introduction. Missile injuries are very serious injuries particularly in the cervical region. They are classified into high and low missile injuries when it involves the cervical spine. In modern guerrilla warfare, one must be aware of ballistic pathology with bullets as well as from explosives. In particular, improvised explosive devices commonly known as IED's play a new and important pathophysiology whether they are suicided vests or roadside bombs. They usually produce severe or lethal injuries and serious neurovascular deficit is frequent. We present the details of 40 patients with local experience on how to handle serious penetrating cervical missile injuries. Methods. All cases were collected from the record of Basrah University Hospital, Iraq. Healthy military gentlemen with ages ranging between 20–35 years were included. Results. 11 patients had bullet injuries and 29patients had fragments of shell injuries. The sites of injuries were 9: C2–C3, 12: C5–C6, 12: C4–C5 and 7: C7-T1. Bullet entrance was anterior in 23 patients, posterior in 7 patients and lateral in 10 patients. The cervical vertebrae were injured in 37 patients at body or lamina level while in 3 patients it was only neural tissue injuries. Missiles were retained in 13 patients. All injuries showed some degree of neurological deficit with quadriplegia in 26 patients. 9 patients presented with very serious injuries. No relation was found between the size of the missile and the extent of damage. Outcome of treatment in all patients was poor. Conclusion. Gunshot wounds only account for approximately one third of penetrating missile injuries in patients who survive and are well enough to receive medical treatment. 62% of patients' cohort were from explosive devices, consistent with data from 2010, where 58% of fatalities were from IED's occurring in foreign soldiers in Afghanistan. We discuss the importance of general supportive measures, generous wound excision, removal of the retained missiles and heavy cover of antibiotics

Although interlaminar endoscopic lumbar discectomy (IELD) is considered to be less invasive than microscopic lumbar discectomy (MLD) in treatment of lumbar herniated nucleus pulposus, the radiologic change of multifidus muscles by each surgery has rarely been reported. The aim of the present study was to compare the quantitative and qualitative changes of multifidus muscles between two surgical approaches and to analyze the correlation between various parameters of multifidus muscles and long term surgical outcome. 21 patients who received MLD and 18 patients who received IELD in a single tertiary hospital were enrolled and their preoperative, postoperative (≤15 days), and follow-up (≥6 months) MRIs were analyzed. The cross-sectional area (CSA) and fatty degeneration rate (FD) were quantitatively estimated at the level of surgery. The correlations among CSA, FD, body mass index, follow-up visual analogue scale(VAS) and Oswestry Disability Index(ODI) were assessed. Mean intervals of postoperative MRI and follow-up MRI from surgery were 3.0±3.7 days and 14.5±10.7 months, respectively. During the follow-up period, VAS was improved from 7.1±1.3 to 2.1±1.8 in MLD and from 8.2±1.4 to 2.2±1.8 in IELD. In cases of MLD, comparing with preoperative MRI, ipsilateral CSA was significantly increased in postoperative MRI (795.6mm. 2. vs. 906.5mm. 2. , p<0.01), but it was not significantly different in follow-up MRI (795.6mm. 2. vs. 814.4mm. 2. , p=1.00). However, in case of IELD, the ipsilateral CSAs in preoperative, postoperative, and follow-up periods were 892.0 mm. 2. , 909.3 mm. 2. , and 900.3 mm. 2. , respectively. These changes were not significant over time (p=0.691). The ipsilateral FDs were not significantly changed between preoperative and follow-up periods in both MLD (21.4% vs. 20.9%, p=0.81) and IELD groups (23.5% vs. 21.8%, p=0.19). The increment of ipsilateral CSA had significant correlations with follow-up ODI (r=−0.368, p=0.02). Comparing with IELD, MLD induced more surgical trauma on multifidus muscle in postoperative period, but the muscular damage was recovered in follow-up period. IELD can minimize surgical trauma on multifidus muscle showing similar pain relief as MLD. Favorable surgical outcome in follow-up period may be related to increment of multifidus muscle volume. Figure 1. (A-C) The multifidus muscles in preoperative, postoperative, and follow-up periods, respectively, in patient with MLD. Comparing with preoperative period, the CSA of right multifidus muscle (ipsilateral side) was increased in postoperative period, but recovered in follow-up period. (D-F) The multifidus muscle in preoperative, postoperative, and follow-up periods, respectively, in patient with IELD. The CSA of left multifidus muscles (ipsilateral side) was not significantly changed over time. Comparing preoperative MRIs with follow-up MRIs, the FDs of multifidus muscles were not significantly changed regardless of surgical technique. Figure 2. The CSA was measured by marking region of interest (ROI) and FD was measured by calculating the rate of pixels beyond the threshold in ROI. All measurements were performed using ImageJ software (version 1.52a, National Institutes of Health, Bethesda, Maryland, USA). For any figures or tables, please contact the authors directly

Introduction. Musculoskeletal diseases are the biggest cause of morbidity worldwide, with low back pain (LBP) being the leading cause. Forty percent of LBP cases are caused by disease of shock absorbers in the spine known as intervertebral discs (IVDs). The IVDs enable the spine to twist and bend, whilst absorbing load during normal daily activities. The durability of this tissue is sustained by the cells of the spine and so during disease or mechanical damage these cells can behave abnormally further damaging the disc and stimulating local nerves causing extreme pain. Degradation of the intervertebral disc (IVD) currently has no preventative treatment; an injectable hydrogel biomaterial could reinforce disc mechanical properties and promote tissue regeneration. Methods and Results. We present an injectable range of hydrogel biomaterials made from water, clay and polymer that set at 37°C. The materials were made at 80°C polymerised in water and stored at 70°C to remain liquid. The physical properties of the materials were assessed using various methods, including mechanical assessment using temperature-controlled rheometry to monitor the liquid-hydrogel transition. Conclusion. Results showed that by changing three factors within the formulation we can produce a range of materials with suitable mechanical and morphological properties for a variety of tissues of the spine. These types of biomaterials have the potential to provide the first efficacious early-mid stage treatment for IVD disease and reduce the cost of LBP on our health services. Conflicts of interest: CS and CLM are named inventors on the patent for NPgel/BGel. Funded by the Medical Research Council and Versus Arthritis UK: SNiPER

Aims

Surgical approaches to cervical ossification of the posterior longitudinal ligament (OPLL) remain controversial. The purpose of the present study was to analyze and compare the long-term neurological recovery following anterior decompression with fusion (ADF) and posterior laminectomy and fusion with bone graft and internal fixation (PLF) based on > ten-year follow-up outcomes in a single centre.

Aims

Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.

Aims

The optimal procedure for the treatment of ossification of the posterior longitudinal ligament (OPLL) remains controversial. The aim of this study was to compare the outcome of anterior cervical ossified posterior longitudinal ligament en bloc resection (ACOE) with posterior laminectomy and fusion with bone graft and internal fixation (PTLF) for the surgical management of patients with this condition.

Aims

This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect.

Aims

The aim of this study was to reassess the rate of neurological, psoas-related, and abdominal complications associated with L4-L5 lateral lumbar interbody fusion (LLIF) undertaken using a standardized preoperative assessment and surgical technique.

Aims

Traumatic central cord syndrome (CCS) typically follows a hyperextension injury and results in motor impairment affecting the upper limbs more than the lower, with occasional sensory impairment and urinary retention. Current evidence on mortality and long-term outcomes is limited. The primary aim of this study was to assess the five-year mortality of CCS, and to determine any difference in mortality between management groups or age.