Aims. The presence of facet tropism has been correlated with an elevated susceptibility to lumbar disc pathology. Our objective was to evaluate the impact of facet tropism on chronic lumbosacral discogenic pain through the analysis of clinical data and finite element modelling (FEM). Methods. Retrospective analysis was conducted on clinical data, with a specific focus on the spinal units displaying facet tropism, utilizing FEM analysis for motion simulation. We studied 318 intervertebral levels in 156 patients who had undergone provocation discography. Significant predictors of clinical findings were identified by univariate and multivariate analyses. Loading conditions were applied in FEM simulations to mimic biomechanical effects on intervertebral discs, focusing on maximal displacement and intradiscal pressures, gauged through alterations in disc morphology and physical stress. Results. A total of 144 discs were categorized as ‘positive’ and 174 discs as ‘negative’ by the results of provocation discography. The presence of defined facet tropism (OR 3.451, 95% CI 1.944 to 6.126) and higher Adams classification (OR 2.172, 95% CI 1.523 to 3.097) were important predictive parameters for discography-‘positive’ discs. FEM simulations showcased uneven stress distribution and significant disc displacement in tropism-affected discs, where loading exacerbated stress on facets with greater angles. During varied positions, notably increased stress and displacement were observed in discs with tropism compared to those with normal facet structure. Conclusion. Our findings indicate that facet tropism can contribute to disc herniation and changes in intradiscal pressure, potentially exacerbating disc degeneration due to altered force distribution and increased mechanical stress. Cite this article: Bone Joint Res 2024;13(9):452–461

Intervertebral disc (IVD) degeneration is a pathological process often associated with chronic back pain and considered a leading cause of disability worldwide. 1. During degeneration, progressive structural and biochemical changes occur, leading to blood vessel and nerve ingrowth and promoting discogenic pain. 2. In the last decades, several cytokines have been applied to IVD cells in vitro to investigate the degenerative cascade. Particularly, IL-10 and IL-4 have been predicted as important anabolic factors in the IVD according to a regulatory network model based in silico approach. 3. Thus, we aim to investigate the potential presence and anabolic effect of IL-10 and IL-4 in human NP cells (in vitro) and explants (ex vivo) under hypoxia (5% O2) after a catabolic induction. Primary human NP cells were expanded, encapsulated in 1.2% alginate beads (4 × 106 cells/ml) and cultured for two weeks in 3D for phenotype recovery while human NP explants were cultured for five days. Afterwards, both alginate and explant cultures were i) cultured for two days and subsequently treated with 10 ng/ml IL-10 or IL-4 (single treatments) or ii) stimulated with 0.1 ng/ml IL-1β for two days and subsequently treated with 10 ng/ml IL-10 or IL-4 (combined treatments). The presence of IL-4 receptor, IL-4 and IL-10 was confirmed in human intact NP tissue (Fig 1). Additionally, IL-4 single and combined treatments induced a significant increase of proinflammatory protein secretion in vitro (Fig. 2A-C) and ex vivo (Fig. 2D and E). In contrast, no significant differences were observed in the secretome between IL-10 single and combined treatments compared to control group. Overall, IL-4 containing treatments promote human NP cell and explant catabolism in contrast to previously reported IL-4 anti-inflammatory performance. 4. Thus, a possible pleiotropic effect of IL-4 could occur depending on the IVD culture and environmental condition. Acknowledgements: This project was supported by the Marie Skłodowska Curie International Training Network “disc4all” under the grant agreement #955735. For any figures and tables, please contact the authors directly

Cite this article: Bone Joint Res 2023;12(3):199–201.

Lumbar fusion remains the gold standard for the treatment of discogenic back pain. Total disc replacement has fallen out of favor in many institutions. Other motion preservation alternatives, such as nucleus replacement, have had limited success and none are commercially available at this time. Two prospective, nonrandomized multicenter studies of lumbar disc nucleus replacement using the PerQdisc 2.0 nucleus replacement device in patients with lumbar discogenic back pain. Early clinical results are presented. A total of 16 patients from 4 international sites (Germany, Paraguay, Canada and Belgium) were enrolled in the trial between May 2019 and February 2021. Data collection points include baseline and postoperatively at 1, 2, 6, and 12 months. Clinical outcome measures were obtained from the Visual Analog Scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), SF-12V2, Analgesic Score (AS), and radiographic assessments. Prospectively gathered data on patient reported outcomes, neurological outcome, surgical results, radiological analysis, and any adverse events. 16 patients had successful implantation of the device. There have been no expulsions of the device. Early postoperative results are available in 13/16 patients at 6 months and 11/16 patients at 12 months. There have been 4 (25%) revision surgeries 3–12 months post implantation between the two trials. 12 of 13 (92%) patients had Minimal Clinically Important Difference (MCID) in ODI at 6 months and 10 of 11 (91%) at 12 months. Mean decrease in ODI from baseline to 12 months was 44.8. At 12 months 8 (73%) patients are not taking pain medication, 1 (9%) patient is taking a narcotic for pain management. 73% of patients are working without restrictions at 12 months post implant. Early clinical and technical results are encouraging. Long term follow up is essential and is forthcoming. Additional patient recruitment and data points are ongoing. FDA/Drug Status Investigational/Not approved

Intervertebral discs (IVDs) degeneration is one of the major causes of back pain. Upon degeneration, the IVDs tissue become inflamed, and this inflammatory microenvironment may cause discogenic pain. Cellular senescence is a state of stable cell cycle arrest in response to a variety of cellular stresses including oxidative stress and adverse load. The accumulation of senescent IVDs cells in the tissue suggest a crucial role in the initiation and development of painful IVD degeneration. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP). The SASP promote matrix catabolism and inflammation in IVDs thereby accelerating the process of degeneration. In this study, we quantified the level of senescence in degenerate and non-degenerate IVDs and we evaluated the potential of two natural compounds to remove senescent cells and promote overall matrix production of the remaining cells. Human IVDs were obtained from organ donors. Pellet or monolayer cultures were prepared from freshly isolated cells and cultured in the presence or absence of two natural compounds: Curcumin and its metabolite vanillin. Monolayer cultures were analyzed after four days and pellets after 21 days for the effect of senolysis. A cytotoxicity study was performed using Alamar blue assay. Following treatment, RNA was extracted, and gene expression of senescence and inflammatory markers was evaluated by real-time q-PCR using the comparative ΔΔCt method. Also, protein expression of p16, Ki-67 and Caspase-3 were evaluated in fixed pellets or monolayer cultures and total number of cells was counted on consecutive sections using DAPI and Hematoxylin. Proteoglycan content was evaluated using SafraninO staining or DMMB assay to measure sulfated glycosaminoglycan (sGAG) and antibodies were used to stain for collagen type II expression. We observed 40% higher level of senescent cells in degenerate compare to the non-degenerate discs form unrelated individuals and a 10% increase when we compare degenerate compare to the non-degenerate discs of the same individual. Using the optimal effective and safe doses, curcumin and vanillin cleared 15% of the senescent cells in monolayer and up to 80% in pellet cultures. Also, they increased the number of proliferating and apoptotic cells in both monolayer and pellets cultures. The increase in apoptotic cell number and caspase-3/7 activity was specific to degenerate cells. Following treatment, mRNA expression levels of SASP factors were decreased by four to 32-fold compared to the untreated groups. Senescent cell clearance decreased, protein expression of MMP-3 and −13 by 15 and 50% and proinflammatory cytokines levels of IL-1, IL-6 and IL-8 by 42, 63 and 58 %. Overall matrix content was increased following treatment as validated by an increase in proteoglycan content in pellet cultures and surrounding culture media. This work identifies novel senolytic drugs for the treatment of IVD degeneration. Senolytic drugs could provide therapeutic interventions that ultimately, decrease pain and provide a better quality of life of patients living with IVDs degeneration and low back pain

Objectives

Interleukin 18 (IL-18) is a regulatory cytokine that degrades the disc matrix. Bone morphogenetic protein-2 (BMP-2) stimulates synthesis of the disc extracellular matrix. However, the combined effects of BMP-2 and IL-18 on human intervertebral disc degeneration have not previously been reported. The aim of this study was to investigate the effects of the anabolic cytokine BMP-2 and the catabolic cytokine IL-18 on human nucleus pulposus (NP) and annulus fibrosus (AF) cells and, therefore, to identify potential therapeutic and clinical benefits of recombinant human (rh)BMP-2 in intervertebral disc degeneration.

Summary. Cytokines produced within the degenerate disc induce expression of neurotrophic factors and pain related peptides which could be important in nerve ingrowth and pain sensitisation leading to low back pain. The intervertebral disc (IVD) is considered the largest aneural and avascular structure within the human body, yet during degeneration vascularisation of the IVD is seen to be accompanied by nociceptive nerves. Low back pain is a highly debilitating condition affecting around 80% of the population, 40% of which are attributed to IVD degeneration. Discogenic pain was largely thought to be a result of irritation and compression of the nerve root, yet recent data suggests that pain may be attributed to the sensitisation of sensory nerves by the synthesis of pain related peptides, calcitonin gene related peptide (CGRP) and substance P. It is known that cytokines and chemokines produced by nucleus pulposus cells elicit various effects including the production of matrix degrading enzymes, and decreased matrix molecules. Here, we investigate the hypothesis that cytokines regulate both neurotrophic factor and pain related peptide synthesis within nucleus pulposus and nerve cells which may elicit algesic effects. Real-Time PCR was performed to investigate gene expression of the neurotrophic factors NGF, BDNF, NT3 and their receptors Trk A, B and C along with Substance P and CGRP on directly extracted RNA from human NP cells and NP cells cultured in alginate for 2 weeks prior to treatment for 48hours with IL-1, IL-6 or TNFα at 0–100ng/mL. Similarly SH-SY5Y neuroblastoma cells were differentiated in retinoic acid for 7 days prior to stimulation with IL-1, IL-6 or TNFα at 0ng/mL and 10ng/mL for 48hours. Immunohistochemistry was used to localise neurotrophic factor receptors Trk A, B and C in both degenerate discs and neuronal cells. NGF expression was present in normal and degenerate disc samples, however only degenerate discs expressed the high affinity receptor TrkA. Similarly Trk B was present in 22% of normal samples increasing to 100% expression within degenerate disc samples. All cytokines increased expression of NGF in NP cells (P≤0.05). TNFα also increased BDNF significantly, whereas no significant affects were seen in NT3 expression in NP cells. Trk B expression was significantly increased by IL-1 and TNFα treatment of NP cells. Conversely Trk C was down regulated by IL-6. Substance P was significantly increased by IL-1 and TNFα treatments whilst IL-6 and TNFα increased CGRP expression in NP cells. In SH-SY5Y cells, IL-1 significantly increased BDNF whilst IL-6 and TNFα failed to induce significant differences in neurotrophic factors. All cytokines increased Trk expression in the nerve cell line; however this failed to reach significance. Immunohistochemistry confirmed the presence of Trk receptors within the neuronal cell line. Here we have demonstrated that a number of cytokines known to be up regulated during disc degeneration and disc prolapse, induce expression of various neurotrophic factors, their receptors and pain related peptides within human NP cells, as well as SH-SY5Y cells. This data suggests that the presence and production of cytokines within the degenerate disc may be responsible for nerve ingrowth and sensitisation of nerves which may result in discogenic pain

Little information is available about the incidence and outcome of incidental dural tears associated with microendoscopic lumbar decompressive surgery. We prospectively examined the incidence of dural tears and their influence on the outcome six months post-operatively in 555 consecutive patients (mean age 47.4 years (13 to 89)) who underwent this form of surgery. The incidence of dural tears was 5.05% (28/555). The risk factors were the age of the patient and the procedure of bilateral decompression via a unilateral approach. The rate of recovery of the Japanese Orthopaedic Association score in patients with dural tears was significantly lower than that in those without a tear (77.7% vs 87.6%; p < 0.02), although there were no significant differences in the improvement of the Oswestry Disability Index between the two groups. Most dural tears were small, managed by taking adequate care of symptoms of low cerebrospinal fluid pressure, and did not require direct dural repair. Routine MRI scans were undertaken six months post-operatively; four patients with a dural tear had recurrent or residual disc herniation and two had further stenosis, possibly because the dural tear prevented adequate decompression and removal of the fragments of disc during surgery; as yet, none of these patients have undergone further surgery.

Cite this article: Bone Joint J 2014;96-B:641–5.

This short contribution aims to explain how intervertebral disc ‘degeneration’ differs from normal ageing, and to suggest how mechanical loading and constitutional factors interact to cause disc degeneration and prolapse. We suggest that disagreement on these matters in medico-legal practice often arises from a misunderstanding of the nature of ‘soft-tissue injuries’.

Introduction. Discogenic pain is associated with ingrowth of blood vessels and nerves, but uncertainty over the extent of ingrowth is hindering development of appropriate treatments. We hypothesise that adult human annulus fibrosus is such a dense crosslinked tissue that ingrowth via the annulus is confined to a) peripheral regions, and b) fissures extending into the annulus. Methods. Disc tissue was examined from 61 patients (aged 37–75 yrs) undergoing surgery for disc herniation, degeneration or scoliosis. 5 µm sections were stained with H&E to identify structures and tissue types. 30 µm frozen sections were examined using confocal microscopy, following immunostaining for CD31 (an endothelial cell marker), PGP 9.5 and Substance P (general and nociceptive nerve markers, respectively). Fluorescent tags were attached to the antibodies. ‘Volocity’ software was used to calculate numbers and total cross-sectional area of labelled structures, and to measure their distance from the nearest free surface (disc periphery, or annulus fissure). Results. Maximum penetration of blood vessels and nerves from the peripheral annulus was 4,800 µm and 2,200 µm respectively. Maximum distance of nerves and vessels from the nearest free surface was 236 µm and 888 µm. Substance P (but not PGP 9.5) was co-localised with blood vessels, and both number and area of Substance P-stained structures were inversely correlated with grade of disc degeneration. Interpretation. Thick sections and fluorescent markers can show reliably where labelled structures are not present. Results therefore support our hypothesis: deep penetration of nerves into the human annulus occurs only if fissures are present. No conflicts of interest. No funding obtained. This abstract has not been previously published in whole or in part; nor has it been presented previously at a national meeting

Introduction. Risk factors for disc degeneration depend on how the condition is defined, i.e. on the specific disc degeneration “phenotype”. We present evidence that there are two major and largely-distinct types of disc degeneration. Methods. The relevant research literature was reviewed and re-interpreted. Evidence. In the . upper. lumbar and thoracic spine, disc degeneration is closely associated with endplate defects and with inflammatory changes in the vertebral bodies. It has a relatively high heritability (i.e. a strong genetic influence), and its incidence does not increase markedly with age. In the . lower. lumbar spine, disc degeneration is closely associated with radial fissures and nucleus herniation. Here it has a relatively low heritability, and a correspondingly stronger association with mechanical loading, and its incidence increases steadily throughout life. Mechanical experiments on cadaveric spines show that endplate fracture and nucleus herniation can be caused by compressive loading, and by bending combined with compression, respectively. Both lesions cause an immediate decompression of the nucleus, so that it becomes difficult to create subsequently the other lesion in the same disc. This suggests distinct phenotypes. Interpretation. The two types of disc degeneration are not entirely distinct, because disc herniation sometimes occurs at upper lumbar levels. Nevertheless, it may be useful to recognise two phenotypes when it comes to explaining and treating discogenic pain. Some other common disc changes (such as water loss and bulging) are attributable to ageing rather than degeneration, whereas disc narrowing probably represents a final common pathway for both types of disc degeneration. Conflicts of Interest. None. Source of Funding. None. This abstract has not been previously published in whole or in part; nor has it been presented previously at a national meeting

Introduction. Severe ‘discogenic’ back pain may be related to the ingrowth of nerves and blood vessels, although this is controversial. We hypothesise that ingrowth is greater in painful discs, and is facilitated in the region of annulus fissures. Methods. We compared tissue removed at surgery from 22 patients with discogenic back pain and/or sciatica, and from 16 young patients with scoliosis who served as controls. Wax-embedded specimens were sectioned at 7μm. Nerves and blood vessels were identified using histological stains, and antibodies to PGP 9.5 and CD31 respectively. Results. Blood vessels were identified in 77% of ‘painful’ discs compared to 44% of scoliotic discs (p=0.013), and they were more common in the anterior anulus compared to the posterior (p=0.026). Maximum penetration of blood vessels from the peripheral anulus was 4.7 mm (in ‘painful’ discs) and 2.0 mm (in control discs), and penetration increased with histological grade of disc degeneration in the ‘painful’ discs (p=0.002). In 16/17 ‘painful’ discs, blood vessels were within 1 mm of an anulus fissure, or the disc periphery. Nerves were found in 36% of ‘painful’ discs (all with blood vessels) and 25% of control discs. Nerve ingrowth was always less than or equal to blood vessel ingrowth, with a maximum observed penetration of 1.5 mm from the annulus periphery. Discussion. In degenerated and painful discs, the ingrowth of nerves appears to follow that of blood vessels, and is facilitated in the region of annulus fissures. No nerves were seen >2mm from the annulus periphery, suggesting that previous reports of nerves in the disc nucleus may refer to vertical growth from a vertebral endplate rather than radial growth through the annulus. Results support the view that discogenic back pain is associated with pain-sensitisation events in the disc periphery. Acknowledgements. Research funded by BackCare. M Stefanakis would like to thank the Greek Institute of Scholarships (I.K.Y) for financial support

Purpose of Study. To review the medium-term results of the Dynesys stabilisation system used in 113 consecutive patients with discogenic back pain. Methods and Results. 113 consecutive patients with discogenic back pain were treated with Dynesys as the sole intervention. Inclusion criteria included mri proven disc degeneration and an improvement in symptoms following an injection into the disc with local anaesthetic and steroid (spinal disc probing). Patients were followed up for a minimum of 5 years, with outcome measures including SF-36, Oswestry disability index (ODI) and visual pain analogue scores (VPAS). Additional factors reviewed included previous spinal operations, complications, loosening and revision rates with subsequent outcomes. Mean pre-operative ODI was 49.5, SF-36 was 37.6 and VPAS back pain was 60.9. At one year post operatively, these scores were 36.9, 49.4 and 39.8, at five years follow up, the scores were 33.3, 51.8 and 40.1 respectively. We note wide variations in our results. Several significant factors appear to contribute to the outcome of surgery. These include undergoing surgery before the age of 43, no more than 2-level disc degeneration, leg pain less than VPAS 4, and no previous spinal surgery. 19 patients had screw loosening evident on plain film x-rays (4 requiring removal), and 2 patients had screw breakages. 19 patients had implant removal for failure and 2 patients went on to have a fusion procedure. Discussion. Dynesys has a role in the treatment of discogenic back pain. Patient selection is important to outcome and we have identified several pre-operative factors that increase the likelihood of success. The effects are present at 1 year postoperatively and are maintained for at least 5 years. There is a significant screw loosening rate and our series had a 17% revision rate

Introduction. Lumbar spinal pain can be a consequence of discogenic pain. After failure of conservative management, lumbar fusions are popular and considered the gold standard. However, these techniques are associated with significant morbidity. A percutaneous trans-sacral technique may address these for L4/L5 and/or L5/S1 alone spinal fusions. Our unit has adopted this technique and presents our initial experience of 51 patients and preliminary results. Method. Patients with a confirmed clinical and radiological evidence of degenerate intervertebral disc with or without prior surgical intervention were selected. Patients with a history of pelvic surgery/radiotherapy were excluded. Data was collected prospectively using the Global Patient Outcome Scoring System and Oswestry Disability Index (ODI) scores at clinical follow-up. Results. 51 patients received the procedure and 30 achieving a minimum of 6 months follow-up. Patients had a median age of 46(range 20-78) and included 19 male and 32 females with on average 40 months of pain. The mean ODI score improved after surgery from pre-operative levels 52.9(SEM 3.0) to 6 month scores of 38.4(SEM 3.9), t(29)=4.2, p<0.0002 . This difference remained statistically significant at 12 month follow-up with a mean ODI scores 34.3 (SEM 5.2), t(18)=4.37, P<0.0004 (Mean difference of 21.1 SEM 4.8). A sub-analysis of confounding factors identified patients with previous surgery, claiming state benefits, pursuing litigation, mainly leg pain and requiring pedicular fusion failed to achieve statistical significance. Patients receiving a 360 degree fusion with facet screws alone improved sooner and achieving a mean difference in ODI score of 27.6(SEM 8.2). Conclusion. Our initial results confirm this to be an effective alternative treatment modality for lumbar spine fusion in the management of primary discogenic back pain. Patients receiving 360 degree fusion and not claiming state benefits or pursuing litigation appear to have a better outcome