Backgrounds and aim. Low back pain resulting from Intervertebral disc (IVD) degeneration is a serious worldwide problem, with poor treatment options available. Notochordal (NC) cells, are a promising therapeutic cell source with anti-catabolic and regenerative effect, however, their behaviour in the harsh degenerate environment is unknown. Thus, we aimed to investigate and compare their physiological behaviour in in vitro niche that mimics the healthy and degenerated intervertebral disc environment. Methodology. Porcine NC cells were encapsulated in 3D alginate beads to maintain their phenotype then cultured in media to mimic the healthy and degenerate disc environment, together with control NC media for 1 week. Following which viability using PI and Calcein AM, RNA extraction and RT-PCR for NC cell markers, anabolic and catabolic genes analysed. Proteomic analysis was also performed using Digiwest technology. Results. A small increase in cell death was observed in degenerated media compared to standard and healthy media, with a further decrease seen when cultured with IL-1β. Whilst no significant differences were seen in phenotypic marker expression in NCs cultured in any media at gene level (ACAN, KRT8, KRT18, FOXA2, COL1A1 and Brachyury). Preliminary Digiwest analysis showed increased protein production for Cytokeratin 18, src and phosphorylated PKC but a decrease in fibronectin in degenerated media compared to standard media. Discussion. Studying the behaviour of the NCs in in vitro conditions that mimic the in vivo healthy or degenerate niche will help us to better understand their potential for therapeutic approaches. The initial work has been then translated to investigate the potential use of iPSCs differentiated into notochordal like cells as potential regenerative cell sources. Conflicts of interest: No conflicts of interest. Sources of funding: This project has received funding from the European Union Horizon 2020 research and innovation programme under grant agreement No 825925

Background. Disability is an important multifaceted construct. Identifying sources of disability could help optimise patient care. The aim of this study was to test an approach that not only estimates severity of disability, but also identifies the source(s) of this disability. Methods. An online survey was used to collect data from a convenience sample, recruited via email and social media invitations. Two generic measures of disability, the 8-item Universal Disability Index (UDI8) and Groningen Activity Restriction Scale (GARS) were used to estimate the prevalence and severity of disability in this sample. Non-zero UDI8 item responses generated conditional sub-questions, in which participants could attribute their activity limitations to one or more sources (pain, fatigue, worry, mood, and other). This allowed for a decomposition of UDI8 scores into source components. Results. 403 participants enrolled; 334 completed all UDI8 and GARS items. Of these, 85.3% (285/334) reported at least one restricted activity via the UDI8, while 43.4% (145/334) reported some reduced independence via the GARS. Disability severity increased with age until approximately 40 years, after which it decreased gradually. Pain component scores were high in all individuals with higher and lower disability severity, whereas fatigue component scores were highest in individuals reporting higher disability severity. Worry, mood, and other component scores were not high at any level of disability severity. Conclusions. This approach should be used to identify the prevalence, severity and sources of disability in the general population and in specific patient groups. Conflicts of interest. No conflicts of interest. Sources of funding. No funding obtained

Background. Current clinical treatment for spinal instability requires invasive spinal fusion with cages and screw instrumentation. We previously reported a novel injectable hydrogel (Bgel), which supports the delivery and differentiation of mesenchymal stem cells (MSCs) to bone forming cells and supports bone formation in vivo. Here, we investigated whether this system could be utilised to induce bone formation within intervertebral disc tissue as a potential injectable spinal fusion approach. Methodology. Bovine and Human Nucleus pulpous tissue explants were injected with Bgel with and without MSCs. Tissue samples were cultured under hypoxia (5%) in standard culture media for 4 weeks. Cell viability, histological assessment of matrix deposition, calcium formation, and cell phenotype analysis using immunohistochemistry for NP matrix and bone markers. Results. Following injection of B-gel into tissue explants following culture for 4 weeks, cells were visualized within the regions of the B-gel. Demonstrating that native cells were able to migrate into regions of B-gel. Increased collagen deposition was seen in tissue explants injected with Bgel, with increased collagen type I and X but decreased collagen type II staining in explants injected with Bgel. Tissue explants, in the absence of Bgel, showed limited calcium deposition, which was increased in B-gel injected explants. Furthermore, disc cells increased expression of bone markers (alkaline phosphatase & osteocalcin), but decreased NP matrix (Aggrecan and Collagen type II) following Bgel injection. Conclusion. This system could have potential to support spinal fusion via direct injection into the disc. Conflict of interest: C Le Maitre & C Sammon are inventors on the hydrogel discussed. Funding: This work was funded by GrowMed Tech Proof of Concept funding

A Core Outcome Set (COS) for treatment of adolescent idiopathic scoliosis (AIS) is essential to ensure that the most meaningful outcomes are evaluated and used consistently. Measuring the same outcomes ensures evidence from clinical trials and routine clinical practice of different treatments can be more easily compared and combined, therefore increasing the quality of the evidence base. The SPINE-COS-AYA project aims to develop a gold standard COS which can be used internationally in research and routine clinical practice to evaluate the treatment (surgical and bracing) of AIS. In this qualitative study, the views of adolescents and young adults with AIS (10-25 years of age), their family members and healthcare professionals in a UK region were sought, via interviews, on treatment outcomes. Participants were purposively recruited from a variety of sources including NHS outpatient clinics and social media. Semi-structured interviews were analysed using thematic analysis. Key findings will be presented, to include potential core outcome domains identified by the different subgroups. The core outcome domains identified in this research programme will subsequently form part of an international consensus survey to agree a COS. In future, if the COS is used by healthcare staff and researchers, it will be easier for everyone, including patients and their families, to assess which treatment works best

Objectives. This study aims to investigate whether bacteria are present in intervertebral discs (IVDs) and their influence. Causality between chronic infection of the IVD and its degenerative process gained great interest recently. Granville Smith et al. (2021) identified 36 articles from 34 research studies investigating bacteria in IVDs, from these 27 studies found, Cutibacterium acnes being the most abundant. However, whether bacteria identified were present in vivo or if they represent contamination remains unclear. Methods. Human IVD tissue was fixed in paraffin and Immunohistochemical stained for Gram-positive bacteria. NP cells in monolayer have been stimulated with LPS (0.1–50 µg/ml) and Peptidoglycan (0.1–50 µg/ml) for 24, 48 and 72 hrs to investigate their influence. The concentration of proinflammatory and catabolic cytokines in the media is being measured using ELISA. RNA extracted and RT-qPCR utilised for factors associated with disc degeneration matrix genes, matrix degrading enzymes, cytokines, neurotrophic factors and angiogenic factors. Results. Bacteria were detected within IVD tissue. Bacteria was internalized by the NP cells and influenced the nuclei morphology. Preliminary results of the exposure of NP cells to bacterial components demonstrate that ADAMTS4 as well as IL-8 were showed an increase in gene expression after LPS and peptidoglycan treatment compared to the non-treated control. Underlining these results, IL-8 protein was increased in treated groups, whereas peptidoglycan treated groups showed a dose dependence. Conclusion. This study demonstrates that Gram positive bacteria are present within the IVD. The exposure of NP cells to peptidoglycans indicates that bacterial components trigger a stress response. Conflicts of Interest: No conflict of interest. Sources of Funding: This project is part of the Disc4All Training network to advance integrated computational simulations in translational medicine, applies to intervertebral disc degeneration and funded by Horizon 2020 (H2020-MSCA-ITN-ETN-2020 GA: 955735)

Background. Intervertebral disc degeneration is implicated as a major cause of chronic lower back pain. Current therapies for lower back pain are aimed purely at relieving the symptoms rather than targeting the underlying aberrant cell biology. As such focus has shifted to development of cell based alternatives. Notochordal cells are progenitors to the adult nucleus pulposus that display therapeutic potential. However, notochordal cell phenotype and suitable culture conditions for research or therapeutic application are poorly described. This study aims to develop a suitable culture system to allow comprehensive study of the notochordal phenotype. Methods & Results. Porcine notochordal cells were isolated from 6 week post natal discs using dissection and enzymatic digestion and cultured in vitro under different conditions: (1)DMEM vs αMEM (2)laminin-521, fibronectin, gelatin and untreated tissue culture plastic (3)2% 02 vs normoxia (4)αMEM (300 mOsm/L) vs αMEM (400 mOsm/L). Notochordal cells were cultured in alginate beads as a control. Adherence, cell viability, morphology and expression of known notochordal markers (CD24, KRT8, KRT18, KRT19 and T) were assessed throughout the culture period. Use of αMEM media and laminin-521 coated surfaces displayed the greatest cell adherence, viability and retention of notochordal cell morphology and gene expression, which was further enhanced through culture in hypoxia and hyperosmolar media mimicking the intervertebral disc niche. Conclusions. Assessment of the therapeutic potential of notochordal cells is potentially valuable to development of a cell based therapy for chronic lower back pain. Our model has provided a system in which notochordal cells can be studied extensively. Conflicts of Interest: None. Funding obtained from the Henry Smith Charity, London

Background. Degeneration of the intervertebral disc (IVD) is a major cause of Low back pain. We have recently reported a novel, injectable liquid L-pNIPAM-co-DMAc hydrogel (NPgel), which promote differentiation of MSCs to nucleus pulposus (NP) cells without the need for additional growth factors. Here, we investigated the behaviour of hMSCs incorporated within the hydrogel injected into NP tissue. Methods. hMSCs were injected either alone or within NPgel, into bovine NP tissue explants and maintained at 5% O. 2. for up to 6wks. Media alone and acellular NPgel were also injected into NP explants to serve as controls. Cell viability was assessed by Caspase 3 immunohistochemistry and the phenotype of injected hMSC was assessed by histology and immunohistochemistry. Mechanical properties were also assessed via dynamic mechanical analysis (DMA). Results. No significant difference in the elastic modulus was observed between NPgel injected NP tissue and media injected controls. CFSe positive hMSCs were identified in all injected tissue samples and cell viability was maintained. Where hMSCs were delivered via NPgel, the hydrogel integrated with native NP tissue and cells producing NP matrix components: aggrecan; collagen type II and chondroitin sulphate. Conclusion. hMSC incorporated within L-pNIPAM-co-DMAc hydrogel and injected into NP explants, integrate with native NP tissue and promote differentiation towards the NP phenotype; thus potentially could be used to regenerate the NP as a treatment strategy for LBP. No conflict of interest. Funding: BMRC, MERI Sheffield Hallam University

Background to the study:. The use of Patient Reported Outcome Measures (PROMs) to measure effectiveness of care, and supporting patient management is being advocated increasingly. PROMs data are often collected using hard copy questionnaires. New technology enables electronic PROM data collection. Purpose of the study:. To identify patient and practitioner perceived opportunities and challenges to implementing electronic PROM data capture as part of the process for developing a PROM phone and online app. Methods:. Interviews were undertaken with patients (N=18), and clinicians (N=46). Patients and clinicians were recruited through practice advertisement, in printed healthcare media, social media, and professional networks. Semi-structured interviews were used. Data were analysed using the Framework approach. Themes, sub-themes, and models were developed from the analysed data. Results:. Patient themes included relevance of data collection, data protection, and confidentiality. Practitioner themes included issues around patient engagement, and relevance to clinical practice. Overall patients were more enthusiastic than clinicians about using PROMs in practice. They welcomed the opportunity to provide feedback, and were prepared to use technology to achieve this. In contrast, clinicians reported concerns that patients would not want to complete PROMs, or may be unable to use electronic devices to achieve this. Other clinicians noted that this was a professional demand and part of reflective practice. Conclusion:. The patients' enthusiasm to contribute data and the clinicians' paternalistic views were contrasting and suggests a greater need for patient centred communication

Background. A cornerstone in treating low back pain (LBP) is the provision of information to patients, and the internet is increasingly being used as a source of health information delivery. However, the effect of and satisfaction with online information have been questioned. Purpose. To develop a multi-item instrument to measure an index score of satisfaction with online information for patients with LBP. Methods. The conceptualization of this patient reported outcome is modelled on the assumption of a formative model. The first draft of the questionnaire was developed based on a previous published interview study of 15 patients and evaluated for face validity by seven experts. The second draft of the questionnaire was pilot-tested in 20 patients to optimize content validity. Patients were recruited from a rehabilitation center and from social media. Results. An eight-item questionnaire was developed after assessing content and face validity. The items were related to design, readability, customization, credibility, usability, and coping. A labelled categorical scale was used for response options. Each item is scored from 0–3, where 0 indicates not at all satisfied, 1 indicates little satisfaction, 2 indicates some satisfaction, and 3 indicates very satisfied giving an overall index score between 0 and 24 points. Conclusion. An eight-item questionnaire measuring satisfaction with an index score from 0–24 points has been developed. The OPSI questionnaire is now being tested for construct validity, reproducibility and interpretation on 150 patients with LBP. No conflicts of interest. Sources of funding: Funded by the Novo Nordic Foundation (NNF17OC0024422)

Background. Mesenchymal stem cells (MSCs) are undergoing evaluation as a potential new therapy for immune and inflammatory-mediated conditions such as IVD degeneration (IDD). Both adipose (ASCs) and bone-marrow (BMSCs) derived MSCs have been widely used in this regard. The optimal tissue source and expansion conditions required to exploit the regenerative capacity of these cells are not yet fully elucidated. In addition the phenotypic response of transplanted cells to the disease environment is not well understood. In this study, ASCs and BMSCs were exposed to a combination of hypoxic conditioning and selected inflammatory mediators, conditions that mimic the microenvironment of the degenerate IVD, in an effort to understand their therapeutic potency for in vivo administration. Methods and Results. Donor-matched ASCs and MSCs were pre-conditioned with either IL-1β (10ng/ml) or TNFα (10ng/ml) for 48 hours under hypoxic conditions (5% O. 2. ). Conditioned media was collected and 45 different immunomodulatory proteins were analysed using human magnetic Luminex® assay. Secreted levels of several key cytokines and chemokines, both pro- and anti-inflammatory, were significantly upregulated in ASCs and BMSCs following the conditioning regime. Under all conditions tested, ASCs expressed significantly higher levels of IL-4, IL-6, IL-10, IL-12, TGF-α, and GCSF compared to BMSCs. Pre-conditioning with TNFα resulted in significantly higher levels of IL-10 while preconditioning with IL-1β resulted in higher levels of IL-6, IL-12 and GCSF. Conclusion. These data suggest that pre-conditioned ASCs may have enhanced therapeutic potential in modulating IVD repair through the increased release of trophic factors that play a role in immunomodulation. Conflicts of interest: None. Sources of funding: Financial support for this research was provided by EU Horizon 2020 RESPINE grant (Project ID# 732163)

Background. Stem cell therapy has been suggested as a potential regenerative strategy to treat IVD degeneration and GDF6 has been shown to differentiate adipose-derived stem cells (ASCs) into an NP-like phenotype. However, for clinical translation, a delivery system is required to ensure controlled and sustained GDF6 release. This study aimed to investigate the encapsulation of GDF6 inside novel microparticles (MPs) to control delivery and assess the effect of the released GDF6 on NP-like differentiation of human ASCs. Methods. GDF6 release from PLGA-PEG-PLGA MPs over 14 days was determined using BCA and ELISA. The effect of MP loading density on collagen gel formation was assessed through SEM and histological staining. ASCs were cultured in collagen hydrogels for 14 days with GDF6 delivered exogenously or via microspheres. ASC differentiation was assessed by qPCR for NP markers, glycosaminoglycan production (DMMB) and immunohistochemistry. Results. GDF6 release from MPs was controlled over 14 days equivalently to exogenous addition. SEM and histology confirmed that MPs were distributed throughout gels and that gel formation was not disrupted. In 3D cultures, GDF6 release from microspheres elicited equivalent ASC differentiation and NP-like matrix formation compared to exogenous delivery in media, indicating activity was not affected by MP encapsulation. Conclusions. This study demonstrates the effective encapsulation and controlled delivery of GDF6, which was able to maintain its activity and induce ASC differentiation into an NP-like phenotype and production of an NP-like ECM. Delivery of GDF6 microspheres in combination with ASCs is a promising strategy for IVD regeneration and treatment of back pain. Conflicts of interest. No conflicts of interest. Sources of funding. We would like to acknowledge UKRMP Acellular Hub, MRC, NIHR Musculoskeletal BRU and The Rosetrees Trust for funding this research

Purpose of study. To evaluate implementation of the Back Skills Training (BeST) programme in clinical practice within the National Health Service (NHS). Background. The BeST programme is a group Cognitive Behavioural Approach (CBA) for people with persistent (≥6 weeks) low back pain (LBP). This intervention has been shown to be clinically and cost-effective in a large pragmatic trial. To aid implementation of the BeST programme, an online training intervention (iBeST) was developed. Methods. iBest was promoted through marketing activities (e.g. conferences, social media, evidence briefs) prior to release and launched in March 2016 for NHS health care professionals. Impact of iBeST is being evaluated by measuring number enrolled, course completion, implementation intention, clinical delivery, perceived competence, attitudes/beliefs towards LBP, knowledge and satisfaction. Data is collected at pre and post-training, 4 months and 12 months after course completion. A service evaluation is also being conducted to measure clinical impact. Patients taking part in the BeST programme as part of routine treatment complete questionnaires at baseline, post-treatment, 3 months and 12 months after the programme to assess pain, disability, recovery, satisfaction and usefulness of BeST. Results. 881 clinicians have enrolled on iBeST and 260 have completed training (target: 250). 28 NHS sites are delivering the BeST programme. 385 and 290 participants have provided baseline and post treatment data respectively (target: 400). Data collection is ongoing. Conclusion. Implementation is challenging but iBeST has been well received by NHS clinicians and we plan to report further results of the impact and service evaluation. Conflict of interest: None. Source of funding: This research is funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care Oxford at Oxford Health NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health

The widespread use of MRI has revolutionised the diagnostic process for spinal disorders. A typical protocol for spinal MRI includes T1 and T2 weighted sequences in both axial and sagittal planes. While such an imaging protocol is appropriate to detect pathological processes in the vast majority of patients, a number of additional sequences and advanced techniques are emerging. The purpose of the article is to discuss both established techniques that are gaining popularity in the field of spinal imaging and to introduce some of the more novel ‘advanced’ MRI sequences with examples to highlight their potential uses.

Cite this article: Bone Joint J 2015;97-B:1683–92.

A self-control ratio, the spine-pelvis index (SPI), was proposed for the assessment of patients with adolescent idiopathic scoliosis (AIS) in this study. The aim was to evaluate the disproportionate growth between the spine and pelvis in these patients using SPI. A total of 64 female patients with thoracic AIS were randomly enrolled between December 2010 and October 2012 (mean age 13 years, standard deviation (sd) 2.17; 9 to 18) and a further 73 healthy female patients with a mean age of 12.4 years (mean age 12.4 years, sd 2.24; 9 to 18), were randomly selected from a normal control database at our centre. The radiographic parameters measured included length of spine (LOS), height of spine (HOS), length of thoracic vertebrae (LOT), height of thoracic vertebrae (HOT), width of pelvis (WOP), height of pelvis (HOP) and width of thorax (WOT). SPI was defined as the ratio LOS/HOP. The SPI and LOT/HOP in patients with AIS showed a significant increase when compared with normal girls (p < 0.001 and p < 0.001 respectively), implying an abnormal pattern of growth of the spine relative to the pelvis in patients with AIS.

No significant difference in SPI was found in different age groups in the control group, making the SPI an age-independent parameter with a mean value of 2.219 (2.164 to 2.239). We also found that the SPI was not related to maturity in the control group.

This study, for the first time, used a self-control ratio to confirm the disproportionate patterns of growth of the spine and pelvis in patients with thoracic AIS, highlighting that the SPI is not affected by age or maturity.

Cite this article: Bone Joint J 2015;97-B:1668–74.

We investigated the incidence of anomalies in the vertebral arteries and Circle of Willis with three-dimensional CT angiography in 55 consecutive patients who had undergone an instrumented posterior fusion of the cervical spine.

We recorded any peri-operative and post-operative complications. The frequency of congenital anomalies was 30.9%, abnormal vertebral artery blood flow was 58.2% and vertebral artery dominance 40%.

The posterior communicating artery was occluded on one side in 41.8% of patients and bilaterally in 38.2%. Variations in the vertebral arteries and Circle of Willis were not significantly related to the presence or absence of posterior communicating arteries. Importantly, 18.2% of patients showed characteristic variations in the Circle of Willis with unilateral vertebral artery stenosis or a dominant vertebral artery, indicating that injury may cause lethal complications. One patient had post-operative cerebellar symptoms due to intra-operative injury of the vertebral artery, and one underwent a different surgical procedure because of insufficient collateral circulation.

Pre-operative assessment of the vertebral arteries and Circle of Willis is essential if a posterior spinal fusion with instrumentation is to be carried out safely.

Cite this article: Bone Joint J 2014;96-B:535–40.

We report on two cases of infective spondylodiscitis caused by Gemella haemolysans in otherwise healthy patients. This organism has only rarely been identified as a cause of bone and joint infection, with only two previous reports of infective spondylodiscitis.

We describe the clinical features, investigations and treatment options.

Discogenic low back pain is a common cause of disability, but its pathogenesis is poorly understood. We collected 19 specimens of lumbar intervertebral discs from 17 patients with discogenic low back pain during posterior lumbar interbody fusion, 12 from physiologically ageing discs and ten from normal control discs. We investigated the histological features and assessed the immunoreactive activity of neurofilament (NF200) and neuropeptides such as substance P (SP) and vasoactive-intestinal peptide (VIP) in the nerve fibres.

The distinct histological characteristic of the painful disc was the formation of a zone of vascularised granulation tissue from the nucleus pulposus to the outer part of the annulus fibrosus along the edges of the fissures. SP-, NF- and VIP-immunoreactive nerve fibres in the painful discs were more extensive than in the control discs. Growth of nerves deep into the annulus fibrosus and nucleus pulposus was observed mainly along the zone of granulation tissue in the painful discs. This suggests that the zone of granulation tissue with extensive innervation along the tears in the posterior part of the painful disc may be responsible for causing the pain of discography and of discogenic low back pain.

Vertebral compression fractures are the most prevalent complication of osteoporosis and percutaneous vertebroplasty (PVP) has emerged as a promising addition to the methods of treating the debilitating pain they may cause.

Since PVP was first reported in the literature in 1987, more than 600 clinical papers have been published on the subject. Most report excellent improvements in pain relief and quality of life. However, these papers have been based mostly on uncontrolled cohort studies with a wide variety of inclusion and exclusion criteria. In 2009, two high-profile randomised controlled trials were published in the New England Journal of Medicine which led care providers throughout the world to question the value of PVP. After more than two decades a number of important questions about the mechanism and the effectiveness of this procedure remain unanswered.