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

Purpose and background. Cauda equina syndrome (CES) leads to nerve compression in the lumbar spine, and requires immediate treatment to prevent permanent neurological dysfunction, including urinary/anorectal incontinence. The consequences for the patient are significant as, in the decade to 2018, CES has cost the NHS £186,134,049. No study has reported patients’ experiences of being managed with suspected CES in an emergency department (ED), and this study explores patients’ experiences and how the NHS can optimise care for patients experiencing this condition. Methods and Results. In this qualitative secondary analysis, 14 participants (aged 23–63 years) with suspected CES were purposively sampled from 4 EDs in England. Online, semi-structed interviews were undertaken (in 2021, during the pandemic), and were audio-recorded and transcribed verbatim. Data were managed using a Framework approach and analysed thematically. Three themes were identified: quality of care; environmental factors; and expectations. The quality of care included managing uncertainty, the importance of communication, appropriate assessment and follow-up care. Environmental factors, including the chairs, waiting times and the busy nature of the ED, negatively impacted patients’ experiences. Furthermore, an expectation gap was identified, as most individuals came to the ED expecting to receive a scan, an accurate diagnosis and a cure. Despite frustrations, patients expressed gratitude towards the ED staff. Conclusion. This study highlights the importance of empathically acknowledging the patient's pain and providing comprehensive assessments and management plans for people attending ED with suspected CES. Optimising the ED environment to minimise patients’ pain and distress while waiting to access care is paramount and overdue. No conflicts of interest.  . Sources of funding. Funding for primary data: Health Education England & National Institute of Health and Care Research (ICA-CDRF-2018-04-ST2-040)

Background. Chronic low back pain (CLBP) is the leading cause of disability worldwide. Immersive virtual reality (IVR) can be delivered using head mounted display (HMD) to interact with 3D virtual environment (VE). IVR has shown promising results in management of chronic pain conditions, using different mechanisms (e.g., exposure to movement and distraction). However, it has not been widely tested for CLBP. Future development of IVR intervention needs inputs from gatekeepers to determine key considerations, facilitators and barriers. This qualitative study aimed to explore views and opinions of physiotherapists about IVR intervention for adults with CLBP. Methods. Four focus groups were conducted online, with 16 physiotherapists. A demonstration of existing IVR mechanisms was presented. The data were transcribed and analysed through descriptive thematic analysis. Results. IVR was thought to be a suitable adjunct for a subgroup of patients who are reluctant to engage with standard care. Motivation to perform challenging physical tasks was believed to be a potential benefit. Safety, possibility of addiction, and transferability of acquired skills from VE to ‘real world’ and hygiene were concerns and the intervention was preferred to be used under clinical supervision. VE personalisation to patient's goal and preference with delivery and progression being gradual depending upon patient's abilities was suggested. Technical knowledge was seen as a facilitator, while cost and technology acceptance were barriers for future implementation. Conclusion. Future studies would need to consider the reported views of physiotherapists to inform development and implementation of IVR intervention for CLBP. Conflicts of interest: No conflict of interest. Sources of funding: Funded by the government of Saudi Arabia

Purpose of the study. The purpose of this project was to evaluate whether OHEIs could facilitate student physiotherapy placement training in their educational outpatient clinics. Background. The National Health Service (NHS) is actively promoting Allied Health Professionals (AHPs) to have a greater role in supporting healthcare delivery. There are challenges to increasing AHP numbers and one of these is providing enough student training placements to meet demand. Methods. This evaluation used quantitative and qualitative methods. The OHEI clinical tutors and students collected activity data Anonymised questionnaires for physiotherapy students examining expectation were completed online before placement and an experience questionnaire after placement. Interviews and focus groups were conducted to investigate the experiences of stakeholders involved in the project. This included physiotherapy and osteopathy students, clinic tutors, and placement coordinators in OHEIs and physiotherapy HEIs. Results. Four universities with physiotherapy courses participated, and 37 students in 2 cohorts completed either five- or six-week placements at three OHEI clinics between April and August 2021. Cohort 1 expressed uncertainties about roles and integration in clinic and with patients. Concerns were addressed for Cohort 2 and physiotherapy student learning experiences were much better with 83% of physiotherapy students satisfied or very satisfied with their placement. Conclusion. The placement of physiotherapists in OHEI clinics is feasible. Careful expectation management is essential. Future sustainability is dependent upon managing costs to the OHEIs as it is unlikely placements will generate income. The learning environment could be made more reciprocal with time and experience leading to better understanding of the different professions and enhanced multidisciplinary working. Conflicts of interest: Dawn Carnes and Carol Fawkes are both trained osteopaths. Sources of funding: Health Education England grant to the Institute of Osteopathy (the professional association for UK osteopaths)

Introduction. The intervertebral disc (IVD) is a highly hydrated and hyperosmotic tissue, water and salt content fluctuate daily due to mechanical loading. Resident IVD cells must adapt to this ever-changing osmotic environment, to maintain normal behaviour. However, during IVD degeneration the disc becomes permanently dehydrated and cells can no longer perform their correct function. Here, we investigated how human nucleus pulposus (NP) cells respond to altered osmolality with regards to cell size and the rate of water permeability, along with the potential involvement of aquaporins (AQPs) and transient receptor potential vanilloid (TRPV) membrane channels. Methods. Water permeability of NP cells exposed to altered osmolality (225–525mOsm/kg) in the presence or absence of AQP and TRPV channel inhibitors was investigated with the cell-permeable calcein-AM fluorescent dye, and cell size determined using microscopy and flow cytometry. Results. Human NP cells modulate their size and water permeability in response to altered osmolality. Inhibiting channel proteins, specifically AQP4, modified NP cell responses to altered osmolality. Conclusion. IVD cells must regulate their size in order to survive and function within an osmotically challenging environment. Here, we demonstrated that NP cells alter their size and permeability in response to altered osmolality which enables them to adapt to their environment. Furthermore these processes were shown to be dependent at least in part by AQP4 expression, which we have previously shown to be decreased during disc degeneration. This potentially highlights novel ways to restore NP cell and overall IVD function by modulating AQPs in the disc. No conflicts of interest. Funded by BMRC, Sheffield Hallam University

Aims. Spinal deformity surgery carries the risk of neurological injury. Neurophysiological monitoring allows early identification of intraoperative cord injury which enables early intervention resulting in a better prognosis. Although multimodal monitoring is the ideal, resource constraints make surgeon-directed intraoperative transcranial motor evoked potential (TcMEP) monitoring a useful compromise. Our experience using surgeon-directed TcMEP is presented in terms of viability, safety, and efficacy. Methods. We carried out a retrospective review of a single surgeon’s prospectively maintained database of cases in which TcMEP monitoring had been used between 2010 and 2017. The upper limbs were used as the control. A true alert was recorded when there was a 50% or more loss of amplitude from the lower limbs with maintained upper limb signals. Patients with true alerts were identified and their case history analyzed. Results. Of the 299 cases reviewed, 279 (93.3%) had acceptable traces throughout and awoke with normal clinical neurological function. No patient with normal traces had a postoperative clinical neurological deficit. True alerts occurred in 20 cases (6.7%). The diagnoses of the alert group included nine cases of adolescent idiopathic scoliosis (AIS) (45%) and six of congenital scoliosis (30%). The incidence of deterioration based on diagnosis was 9/153 (6%) for AIS, 6/30 (20%) for congenital scoliosis, and 2/16 (12.5%) for spinal tuberculosis. Deterioration was much more common in congenital scoliosis than in AIS (p = 0.020). Overall, 65% of alerts occurred during rod instrumentation: 15% occurred during decompression of the internal apex in vertebral column resection surgery. Four alert cases (20%) awoke with clinically detectable neurological compromise. Conclusion. Surgeon-directed TcMEP monitoring has a 100% negative predictive value and allows early identification of physiological cord distress, thereby enabling immediate intervention. In resource constrained environments, surgeon-directed TcMEP is a viable and effective method of intraoperative spinal cord monitoring. Level of evidence: III. Cite this article: Bone Joint J 2021;103-B(3):547–552

Aims. Intraoperative 3D navigation (ION) allows high accuracy to be achieved in spinal surgery, but poor workflow has prevented its widespread uptake. The technical demands on ION when used in patients with adolescent idiopathic scoliosis (AIS) are higher than for other more established indications. Lean principles have been applied to industry and to health care with good effects. While ensuring optimal accuracy of instrumentation and safety, the implementation of ION and its associated productivity was evaluated in this study for AIS surgery in order to enhance the workflow of this technique. The aim was to optimize the use of ION by the application of lean principles in AIS surgery. Methods. A total of 20 consecutive patients with AIS were treated with ION corrective spinal surgery. Both qualitative and quantitative analysis was performed with real-time modifications. Operating time, scan time, dose length product (measure of CT radiation exposure), use of fluoroscopy, the influence of the reference frame, blood loss, and neuromonitoring were assessed. Results. The greatest gains in productivity were in avoiding repeat intraoperative scans (a mean of 248 minutes for patients who had two scans, and a mean 180 minutes for those who had a single scan). Optimizing accuracy was the biggest factor influencing this, which was reliant on incremental changes to the operating setup and technique. Conclusion. The application of lean principles to the introduction of ION for AIS surgery helps assimilate this method into the environment of the operating theatre. Data and stakeholder analysis identified a reproducible technique for using ION for AIS surgery, reducing operating time, and radiation exposure. Cite this article: Bone Joint J. 2020;102-B(1):5–10

Aims. Inflammatory response plays a pivotal role in the pathophysiological process of intervertebral disc degeneration (IDD). A20 (also known as tumour necrosis factor alpha-induced protein 3 (TNFAIP3)) is a ubiquitin-editing enzyme that restricts nuclear factor-kappa B (NF-κB) signalling. A20 prevents the occurrence of multiple inflammatory diseases. However, the role of A20 in the initiation of IDD has not been elucidated. The aim of the study was to investigate the effect of A20 in senescence of TNF alpha (TNF-α)-induced nucleus pulposus cells (NPCs). Methods. Immunohistochemical staining was performed to observe the expression of A20 in normal and degenerated human intervertebral discs. The NPCs were dissected from the tail vertebrae of healthy male Sprague-Dawley rats and were cultured in the incubator. In the experiment, TNF-α was used to mimic the inflammatory environment of IDD. The cell viability and senescence were examined to investigate the effect of A20 on TNF-α-treated NPCs. The expression of messenger RNA (mRNA)-encoding proteins related to matrix macromolecules (collagen II, aggrecan) and senescence markers (p53, p16). Additionally, NF-κB/p65 activity of NPCs was detected within different test compounds. Results. The expression of A20 was upregulated in degenerate human intervertebral discs. The A20 levels of NPCs in TNF-α inflammatory microenvironments were dramatically higher than those of the control group. TNF-α significantly decreased cell proliferation potency but increased senescence-associated beta-galactosidase (SA-β-Gal) activity, the expression of senescence-associated proteins, the synthesis of extracellular matrix, and G1 cycle arrest. The senescence indicators and NF-κB/p65 expression of A20 downregulated group treated with TNF-α were significantly upregulated compared to TNF-α-treated normal NPCs. Conclusion. A20 has a self-protective effect on the senescence of NPCs induced by TNF-α. The downregulation of A20 in NPCs exacerbated the senescence of NPCs induced by TNF-α. Cite this article:Bone Joint Res. 2020;9(5):225–235

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CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration.

Purpose. Clinical guidelines identify a clear role for managing back pain with structured exercise. Pilates is a commonly recommended modality, however, Pilates-specific research is limited. Research suggests the patient-practitioner relationship may be important in managing persistent low back pain, although further research is needed to evaluate its impact on outcomes. The purpose of this study was to identify the components of the relationship between Pilates teachers and clients with persistent low back pain. Methods and Results. This qualitative study used a multi-site, ethnographically-informed methodology. Data collection included observation of 24 Pilates sessions at eight sites across the South of England, and 19 semi-structured interviews with Pilates teachers and clients with persistent low back pain. Data were audio-recorded, transcribed verbatim and analysed thematically. From the interviews and observations, ten themes emerged, of which four related to components of the relationship: (1) ‘being known’; (2) support; (3) teacher expertise; and (4) mastery of exercises, facilitated by the teacher. Key influences on the relationship were identified in four themes: (5) professional identity of Pilates teachers; (6) health perceptions; (7) social influences such as group dynamic; and (8) service perceptions. An additional two themes described the perceived impact of the relationship: (9) feelings of safety; and (10) ‘feeling good’. Conclusion. These findings demonstrate the complex, multi-faceted interaction that occurs during Pilates sessions that includes instruction, demonstration, verbal and tactile feedback. This study illustrates the perceived importance of Pilates teachers in providing a safe environment for clients with persistent low back pain to exercise. No conflicts of interest. No funding obtained

Introduction. Injectable hydrogels via minimally invasive surgery offer benefits to the healthcare system, reduced risk of infection, scar formation and the cost of treatment. Development of new treatments with the use of novel biomaterials requires significant pre-clinical testing and must comply with regulations before they can reach the bedside. In the European economic area (EEA) one of the first hurdles of this process is attaining the CE marking which protects the health, safety and environmental aspects of a product. Implanted materials fall under the class III medical device EU745 regulation standards. To attain the CE marking for a product parties must provide evidence of the materials safety with an investigational medicinal product dossier (IMPD). Methods and Results. We have been working to develop a new thermoresponsive injectable biomaterial hydrogel (NPgel) for the treatment of intervertebral disc (IVD) disease. A large part of the IMPD requires information on how the hydrogel physical properties change over time in bodily conditions. We have been studying 6 batches of NPgel over 18 months, tracking the materials wet/ dry weight, structure and composition. To date we have found that NPgel in liquids more similar to the body (with protein and salts) appear to be stable and safe, whilst those in distilled water swell and disintegrate over time. Subtle long-term changes to the material composition were found and we are currently investigating its ramifications. Conclusion. The study highlights the need to test materials in detail in physiologically representative environments before approaching the bedside and demonstrates promise for NPgel as a suitable CE candidate. 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

Introduction. We have developed a new synthetic hydrogel that can be injected directly into the intervertebral disc (IVD) without major surgery. Designed to improve fixation of joint prosthesis, support bone healing or improve spinal fusion, the liquid may support the differentiation of native IVD cells towards osteoblast-like cells cultured within the hydrogel. Here we investigate the potential of this gel system (Bgel) to induce bone formation within intervertebral disc tissue. Methods. IVD tissue obtained from patients undergoing discectomy, or cadaveric samples, were cultured within a novel explant device. The hydrogel was injected, with and without mesenchymal stem cells (MSCs), and cultured under hypoxia, to mimic the degenerate IVD environment, for 4 weeks. Explants were embedded to wax and native cellular migration into the hydrogel was investigated, together with cellular phenotype and matrix deposition. Results. Increased collagen deposition was seen in tissue explants injected with Bgel, with evidence of elevated native cell migration towards the hydrogel. Increased collagen staining was seen in explants injected with Bgel together with MSCs. Alizarin red staining was utilised to investigate calcium deposition. Tissue explants, in the absence of Bgel, showed limited calcium deposition. This was increased in hydrogel-treated samples, with large clumping regions in the tissue that was injected with Bgel and MSCs. Conclusion. The injection of our synthetic hydrogel into disc tissue explants increased the amount of collagen and calcium deposition. This was further enhanced by the incorporation of MSCs, suggesting the promotion of bone formation. Current work is investigating phenotypic markers for bone formation within these tissues. CS and CLM have a patent on the hydrogel system described in this abstract. Funded by EPSRC and Grow MedTech

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)

Purpose of study and background. Low back pain affects 80% of the population at some point in their lives with 40% of cases attributed to intervertebral disc (IVD) degeneration. A number of potential regenerative approaches are under investigation worldwide, however their translation to clinic is currently hampered by an appropriate model for testing prior to clinical trials. Therefore, a more representative large animal model for IVD degeneration is needed to mimic human degeneration. Here we investigate a caprine IVD degeneration model in a loaded disc culture system which can mimic the native loading environment of the disc. Methods and Results. Goat discs were excised and cultured in a bioreactor under diurnal, simulated-physiological loading (SPL) conditions, following 3 days pre load, IVDs were degenerated enzymatically for 2hrs and subsequently loaded for 10 days under physiological loading. A PBS injected group was used as controls. Disc deformation was continuously monitored and changes in disc height recovery quantified using stretched-exponential fitting. Histological staining was performed on caprine discs to assess extracellular matrix production and immunohistochemistry performed to determine expression of catabolic protein expression. The injection of collagenase and cABC induced mechanical behavior akin to that seen in human degeneration. A decrease in collagens and glycosaminoglycans (GAGs) was seen in enzyme injected discs, which was accompanied by increased cellular expression for degradative enzymes and catabolic cytokines. Conclusion. This model provides a reproducible model of IVD degeneration which mimics human degeneration. This model allows the testing of biomaterials and other potential treatments of IVD degeneration on a scale more representative of the human disc. There are no conflicts of interest. Funded by MRC and Versus Arthritis

Purpose of study and background. IVD degeneration is a major cause of Low back pain. We have previously reported an injectable hydrogel (NPgel), which induces differentiation of human MSCs to disc cells and integrates with NP tissue following injection in vitro. However, the translation of this potential treatment strategy into clinic is dependent on survival and differentiation of MSCs into disc cells within the degenerate IVD. Here, we investigated the viability and differentiation of hMSCs incorporated into NPgel cultured under conditions mimicking the healthy and degenerate microenvironment of the disc. Methods and Results. MSCs were cultured in NP gel under 5% O. 2. in either: standard culture (DMEM, pH7.4); healthy disc (DMEM, pH7.1); degenerate disc (low glucose DMEM, pH6) or degenerate disc plus IL-1β. Following 4 weeks histological staining and immunohistochemical analysis investigated viability, ECM synthesis and matrix degrading enzyme expression. Here we have shown that viability and NP cell differentiation of MSCs incorporated within NPgel was mostly unaffected by treatment with conditions such as low glucose, low pH and the presence of cytokines, all regarded as key contributors to disc degeneration. In addition, the NPgel was shown to prevent MSCs from displaying a catabolic phenotype with low expression of degradative enzymes, highlighting the potential of NPgel to differentiate hMSCs and protect them from the degenerate disc microenvironment. Conclusion. The NPgel described here not only has the potential to provide mechanical support and deliver MSCs for regeneration of the IVD but also may simultaneously function to protect delivered hMSCs from the catabolic environment in the degenerate IVD. C Le Maitre and C Sammon hold a patent for the hydrogel described. Funded by MRC and Versus Arthritis

Study Aim. To design an educational resource for people with lower back pain (LBP) using creative co-production. Background. Beliefs associated with a traditional biomedical view of LBP can be a barrier to recovery. Education that reframes the problem as complex and multifactorial may help patients except and engage with more positive attitudes and behaviours. Creative co-production provides a different approach to research intervention development. It encourages a collaborative problem-solving and non-hierarchical approach to knowledge mobilisation. Method. A four-phased approach to creative co-production was used based on methods developed by the Translating Knowledge into Action (TK2A) theme of NIHR CLAHRC YH. Service users and providers were brought together in a series of workshops. Initially the lived experience of LBP was explored to generate a shared understanding of the complexities of living with and managing LBP. Then activities designed to promote divergent and convergent thinking were used for idea generation. From these ideas a series of contextually sensitive prototypes were developed and tested on a small scale. Following further iterations the final prototype, ready for implementation, was presented to all key stake holders. Results. The project produced a new interactive educational resource prototype to promote positive behaviours and attitudes for people living with LBP that can be accessed early on in the health care journey. Conclusion. The creative methods applied in this project allowed patients and staff to work together, flattening hierarchies to produce pragmatic and contextually specific outputs fit for purpose in the complex clinical environment. Project funding: Sheffield Teaching Hospitals Charitable Trust supported by National Institute for Health Research Collaborations for Leadership in Applied Research and Care Yorkshire and Humber (NIHR CLAHRC YH). No conflicts of interest

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To systematically evaluate whether bracing can effectively achieve curve regression in patients with adolescent idiopathic scoliosis (AIS), and to identify any predictors of curve regression after bracing.

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This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD).

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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.

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.