Painful Disc Research Articles

Identification of potentially painful disc fissures in magnetic resonance images using machine-learning modelling

PurposeIt is suggested that non-specific low back pain (LBP) can be related to nerve ingrowth along granulation tissue in disc fissures, extending into the outer layers of the annulus fibrosus. Present study aimed to investigate if machine-learning modelling of magnetic resonance imaging (MRI) data can classify such fissures as well as pain, provoked by discography, with plausible accuracy and precision.MethodsThe study was based on previously collected data from 30 LBP patients (age = 26–64 years, 11 males). Pressure-controlled discography was performed in 86 discs with pain-positive discograms, categorized as concordant pain-response at a pressure ≤ 50 psi and for each patient one negative control disc. The CT-discograms were used for categorization of fissures. MRI values and standard deviations were extracted from the midsagittal part and from 5 different sub-regions of the discs. Machine-learning algorithms were trained on the extracted MRI markers to classify discs with fissures extending into the outer annulus or not, as well as to classify discs as painful or non-painful.ResultsDiscs with outer annular fissures were classified in MRI with very high precision (mean of 10 repeated testings: 99%) and accuracy (mean: 97%) using machine-learning modelling, but the pain model only demonstrated moderate diagnostic accuracy (mean accuracy: 69%; precision: 71%).ConclusionThe present study showed that machine-learning modelling based on MRI can classify outer annular fissures with very high diagnostic accuracy and, hence, enable individualized diagnostics. However, the model only demonstrated moderate diagnostic accuracy regarding pain that could be assigned to either a non-sufficient model or the used pain reference.

Predictors of discogenic pain in magnetic resonance imaging: a retrospective study of provocative discography performed by posterolateral approach.

BackgroundProvocative discography (PD) is a test that is useful in diagnosing discogenic pain (DP). In this study, to diagnose DP, we used a posterolateral approach of needle placement and followed pressure criteria laid down by the Spine Intervention Society. The aim was to identify the correlation between magnetic resonance imaging (MRI) findings (desiccation, high intensity zone and change in shape and size of the disc) and the results of PD.MethodsRecords of 50 patients who underwent PD for DP were analyzed. A total of 109 PDs were performed, with 54 suspect and 55 control discs. Alternate pain generators were ruled out.ResultsA total of 35 suspect discs were positive on PD. The mean disc pressure in the suspect disc was 31.9 ± 7.9 psi (range, 15-44). Of the 50 patients who underwent PD, 35 had positive MRI findings. A significant positive correlation was found only between disc desiccation and discography result (r = 0.6, P < 0.001). Logistic regression analysis revealed that only desiccation successfully predicted the result of discography (OR = 26.5, P < 0.001); a high intensity zone and a disc protrusion/extrusion had an OR 2.3 and 1.24, respectively. Disc desiccation of Pfirmann grade 3 or more had a sensitivity and specificity of 0.93 and 0.64 respectively in identifying painful discs; the positive likelihood ratio was 2.58 while the negative likelihood ratio was 0.11.ConclusionsIn patients with DP, disc desiccation is the most useful MRI feature that predicts a painful disc on PD.

Intradiscal quantitative chemical exchange saturation transfer MRI signal correlates with discogenic pain in human patients

Low back pain (LBP) is often a result of a degenerative process in the intervertebral disc. The precise origin of discogenic pain is diagnosed by the invasive procedure of provocative discography (PD). Previously, we developed quantitative chemical exchange saturation transfer (qCEST) magnetic resonance imaging (MRI) to detect pH as a biomarker for discogenic pain. Based on these findings we initiated a clinical study with the goal to evaluate the correlation between qCEST values and PD results in LBP patients. Twenty five volunteers with chronic low back pain were subjected to T2-weighted (T2w) and qCEST MRI scans followed by PD. A total of 72 discs were analyzed. The average qCEST signal value of painful discs was significantly higher than non-painful discs (p = 0.012). The ratio between qCEST and normalized T2w was found to be significantly higher in painful discs compared to non-painful discs (p = 0.0022). A receiver operating characteristics (ROC) analysis indicated that qCEST/T2w ratio could be used to differentiate between painful and non-painful discs with 78% sensitivity and 81% specificity. The results of the study suggest that qCEST could be used for the diagnosis of discogenic pain, in conjunction with the commonly used T2w scan.

Viable Disc Tissue Allograft Supplementation; One- and Two-level Treatment of Degenerated Intervertebral Discs in Patients with Chronic Discogenic Low Back Pain: One Year Results of the VAST Randomized Controlled Trial

Background: A viable disc tissue allograft has been developed to supplement tissue loss associated with degenerative lumbar disc disease and the development of chronic discogenic lower back pain. Objectives: Viable disc allograft was injected into painful degenerated discs to evaluate safety and determine whether it can improve pain and function. Study Design: Patients received an active treatment of allograft or saline, or continued with nonsurgical management (NSM). Prior to entering the study, patients had back pain for a minimum of 6 months before treatment that was recalcitrant to nonoperative treatment modalities. Standardized outcome measures were used to evaluate the patient’s condition before and after treatment. Primary endpoints included improvement in Oswestry Disability Index (ODI) and Visual Analog Scale of Pain Intensity (VASPI). Conventional radiographs and magnetic resonance imaging scans were used to assess disc space height and spinal alignment, and to determine the degree of disc degeneration. Patients were followed for one year after enrollment. The NSM group could cross over to the allograft group after 3 months. Setting: This multicenter trial was completed in outpatient surgical centers and office injection suites. A total of 218 patients with chronic low back pain secondary to single-level or 2-level degenerative disc disease were enrolled. Inclusion criteria included pretreatment VASPI &gt;= 40 mm, ODI score &gt;= 40 and symptoms present longer than 6 months. Patients were blinded and randomized to receive intradiscal injections of either viable disc allograft or saline. Patients randomized to the NSM group continued existing treatment. Patients were assessed at 6 and 12 months. Adverse events (AEs) were continually assessed. Methods: The VAST trial is a prospective, multicenter, blind, randomized clinical trial (RCT) for patients with single-level or 2-level degenerative lumbar disc disease. Results: At 12 months, clinically meaningful improvements in mean VASPI and ODI scores were achieved in the investigational allograft and saline groups. A responder analysis demonstrated a clinically meaningful reduction in ODI of &gt;= 15 points at 12 months that was statistically significant; 76.5% of patients randomized to allograft were responders (P = 0.03) compared to 56.7% in the saline group. A responder group characterized by a ? 20 point reduction in pain at 12 months achieved a statistically significant reduction in pain compared to the saline group (P = 0.022). In the allograft group, 11 safety adverse events occurred in 141 patients (3.5%) and there were no persistently symptomatic AEs. Limitations: Limitations of this study include a comparison to saline that has been shown to be more representative of an active comparator as opposed to a placebo. In addition, 36 patients were lost to follow-up; this loss resulted in the saline and NSM/crossover groups being smaller than the predetermined group size to have an appropriately powered analysis. Conclusions: This large, prospective blinded RCT demonstrated safety and efficacy results indicating that viable disc tissue allograft may be a beneficial nonsurgical treatment for patients who have chronically painful lumbar degenerative discs. Further studies would be optimal to confirm efficacy Key words: Viable disc tissue allograft, discogenic back pain, allograft supplementation, degenerative disc disease, low back pain, intervertebral disc, intradiscal injection

Imaging Analysis of the High-Intensity Zone on Lumbar Spine Magnetic Resonance Images: Classification, Features and Correlation with Low Back Pain.

AimEarly studies suggested that the high-intensity zone (HIZ) on lumbar MRI was a diagnostic sign of painful internal disc disruption (IDD). However, recent studies have questioned its diagnostic value. This study is conducted to explore imaging features of HIZ and to investigate the correlation between these characteristics and low back pain (LBP), further studying the predictive value of HIZ.MethodsA retrospective study of 1188 cases was performed. MR images were read and analyzed by two experienced, blinded radiologists.ResultsA total of 575 (48.4%) individuals exhibited HIZ. The prevalence of posterior HIZ (32.3%) was significantly higher than that of anterior HIZ (23.6%; P < 0.01). Round type was the most common shape (61.0%) on sagittal view. Only 37 HIZs (4.6%) were identified on axial views. A total of 263 HIZ discs (32.5%) were found to have additional diagnostic signs of IDD, which is difficult to distinguish from the annulus fibrosus. In subjects with consecutive slides showing HIZ, the incidence of LBP was significantly higher than in single-slide HIZ individuals (58.0% vs 48.6%, P < 0.05).ConclusionMRI-visualized HIZ is a highly valuable method of screening for lumbar IDD. It is demonstrated that consecutive-slide HIZ was a more reliable indicator for discogenic LBP than single-slide HIZ.

Evaluation of the efficiency of different treatment modalities in individuals with painful temporomandibular joint disc displacement with reduction: a randomised controlled clinical trial

The aim of the study was to investigate and compare short and long-term effects of occlusal splints (OS), ultrasound (US), and high-intensity laser therapy (HILT) in patients with painful temporomandibular joint (TMJ) disc displacement with reduction (DDWR). This prospective, randomised, single-blinded, controlled clinical study was conducted on patients with DDWR at a university oral and maxillofacial surgery clinic. A total of 140 patients were allocated randomly to four groups (OS, US, HILT, and control), with 35 patients in each. Patients were evaluated for pain, range of motion of the jaw, disability, and quality of life. A total of 132 patients completed the study. In all treatment groups (OS, US, and HILT), a significant improvement was observed in terms of pain, function, disability, and quality of life, at both weeks four and 12 compared with the control group (p < 0.001). Improvements in VAS pain and maximum mouth opening were not significantly different between the treatment groups. However, compared with the OS group, there was a significant improvement in the HILT and US groups in terms of total Oral Health Impact Profile (OHIP-14) and Jaw Functional Limitation Scale-20 (JFLS-20) scores at week four, but no difference between the groups at week 12. The results of this study show that OS, US, and HILT are effective treatments for pain and functional jaw movements in patients with DDWR. HILT, a new method, can be an alternative treatment in cases of TMD.

P37. MRI disc spectroscopy, a new diagnostic opportunity regarding biochemical evaluation of disc biology

<h3>BACKGROUND CONTEXT</h3> Chronic low back pain (CLBP) patient management is plagued by the inability to reliably and accurately identify painful discs using conventional diagnostic tools such as MRI (in particular, in the absence of Modic signs). However, a new use of MR spectroscopy (MRS) now enables the ability to non-invasively measure disc chemistries - painful acids (eg, lactate), and structural matrix constituents (eg, proteoglycan, and collagen) - as biomarkers for degenerated and painful discs. A prior clinical study showed >90% success rate for fusion and/or TDR surgeries (Sx) at MRS-diagnosed painful discs, vs <60% success when an MRS-diagnosed painful disc was left untreated. <h3>PURPOSE</h3> This current study investigates the clinical outcomes from using disc-MRS to evaluate minimal-invasive and conservative care treatments in CLBP patients. <h3>STUDY DESIGN/SETTING</h3> Prospective study to evaluate the clinical outcome of a MR spectroscopy based treatment (conservative/operative). <h3>PATIENT SAMPLE</h3> A total of 105 discs were examined with MRS in 17 male patients and 13 female patients. <h3>OUTCOME MEASURES</h3> VAS, ODI. <h3>METHODS</h3> For the first time in Europe in 2018, a new "Nociscan-LS" MRS exam protocol was performed (1-center) using a SIEMENS 3T scanner on 30 patients with suspected discogenic back pain. A commercially available "Nocigram-LS" report provided post-processed MRS data for painful disc diagnosis (Nocimed Inc., CE Marked; post-market registry). There were 105 discs examined in 17 male patients and 13 female patients (previous operations in 7 patients: PRP therapy, ozone therapy, nucleoplasty and micro discectomy). Outcomes from MRS-informed operative and conservative care treatments, in de novo patients, were assessed using standard VAS (back-pain) and ODI measures. <h3>RESULTS</h3> Nocigram results indicated pain-relevant chemical changes in at least one lumbar disc in 26 patients. Based on these results: 8 patients were invasively treated at the affected disc (5 nucleoplasty, 3 PRP); 16 were treated conservatively; and discogenic pain was excluded in 4. Significant improvement was reported by 7/8 surgical patients at only 6 weeks and 3 months, and by all 8/8 at 9 months (preop: VAS 7.6, ODI 56.7; 6 w: VAS 2.6, ODI 34.7; 3 m: VAS 1.9, ODI 16; 6 m: VAS 1.8, ODI 16; 9 m: VAS1.7, ODI 16). 15/16 patients who received a targeted conservative therapy, also based on the disc-specific Nocigram MRS results, reported significant improvement (pre-treatment: VAS 5.6, ODI 36.5; 6 w: VAS 1.8, ODI 12; 3 m: VAS 1.2, ODI 8.3; 6 m: VAS 1.3, ODI 10; 9 m: VAS 1, ODI 8). <h3>CONCLUSIONS</h3> 23/24 (96%) of all patients treated according to MRS-based Nocigram diagnostic results had successful outcomes by 3-9 months. This confirms prior reported high success rate for fusion/TDR following MRS diagnosis, while now extending that for the first time to less invasive and conservative care approaches. This suggests non-invasive MRS of degenerative pain biomarker changes in lumbar discs is a landmark inflection point in spine care and is readily adoptable via brief extensions of otherwise standard MRI exams. By quantifying disc pain and degeneration biomarkers, Nocigram enables improved treatment algorithms, including adjacent segment risk assessment in surgery planning. Additionally, Nocigram is a gateway to support future innovations such as cell therapy, and also open new doors into the research of discogenic spinal disorders. <h3>FDA DEVICE/DRUG STATUS</h3> Unavailable from authors at time of publication.

58. Viable disc tissue allograft supplementation in the treatment of degenerated intervertebral discs the one-year results of a randomized control trial

58. Viable disc tissue allograft supplementation in the treatment of degenerated intervertebral discs the one-year results of a randomized control trial

The Prevalence of Temporomandibular Disorders and Dental Attrition Levels in Patients with Posterior Crossbite and/or Deep Bite: A Preliminary Prospective Study.

Background The prevalence of various temporomandibular disorders (TMD) and the severity of attrition in patients with either bilateral or unilateral deep bite and/or posterior crossbite has not been established, nor has the effect of one year of orthodontic treatment on TMD. Methods Of 310 patients presenting with suspected TMD, 160 were diagnosed with various TMD and 150 were TMD-free. Diagnosis was according to the Axis I of the Diagnostic Criteria for TMD. All participants underwent a dental examination, and 100 patients were reevaluated after one year of orthodontic treatment. Fisher's exact test and the proportion test with Bonferroni's correction were used for the categorical univariate analysis. Results There was a significant association (P < 0.001) between deep bite and dental attrition (wear), but not between crossbite and/or deep bite in patients diagnosed with either painful TMD or disc displacement. The risk of sustaining painful TMD when crossbite presented simultaneously on the anterior and the posterior dentition was 2.625-fold greater than when it presented with a normal bite, although this difference was not significant (P=0.286) due to the lack of statistical power. There was no significant sex-related association between the occurrence of either painful TMD or disc displacement. A reduction in TMD findings was demonstrated after one year of treatment, but no statistical power was reached due to the small sample size. Conclusions Deep bite may be related to dental wear but not to pain from TMD and/or disc displacement. Only crossbite that presents simultaneously on the anterior and the posterior dentition (mixed X-bite) may have some effect on the level of pain in TMD, but not on in the prevalence of disc displacement. Confirmation of these conclusions by well-designed studies on larger patient groups is warranted. There was a clinically significant improvement in TMD findings after one year of treatment.

Changes in jaw and neck muscle coactivation and coordination in patients with chronic painful TMD disk displacement with reduction during chewing

The treatment of a complex temporomandibular disorder (TMD), such as disk displacement with reduction (DDR) associated with arthralgia and myalgia, may depends on understanding the impairments in muscle function. The aim of this study was to investigate the behavior of the anterior temporalis, masseter and sternocleidomastoid muscles in the time and frequency domains during chewing in patients with chronic painful TMD-DDR using electromyographic (EMG) analysis. Thirty-three patients who met the diagnostic criteria for TMD and 32 volunteers without TMD (control group) underwent clinical examination, chewing pattern classification and EMG analysis. For the EMG analyses, the side of habitual unilateral chewing, as determined by the chewing pattern classification, was selected for recording; in cases of bilateral chewing, the recording side was randomly selected. The EMG-EMG coherence function and EMG-EMG transfer function (gain and phase) values were obtained at the first chewing frequency peak, and the working-side masseter signal was used as a reference in the analyses of the other muscles. Compared to the control group, the TMD group showed a longer chewing stroke duration (P = 0.01) as well as changes in the coactivation and coordination strategies of the jaw muscles, evidenced by greater relative energy expenditure (P< 0.01) and impaired differential recruitment (P< 0.05) and coherence (P< 0.01). Delays in peak and temporal asynchrony occurred in the jaw and neck muscles (P< 0.05). Patients with chronic painful TMD-DDR during chewing presented changes in the jaw and neck muscles, with more compromised function of the former, which are specific to chewing.

158. The effects of a single injection of NTG-101 upon neurotrophin expression in a canine model of degenerative disc disease

BACKGROUND CONTEXT In normal intervertebral discs the outer annulus has rich innervation that is necessary to inform reflexive postural muscular activity and to serve as response elements in the event of disease/injury. However, it has been shown that in degenerative, painful discs there is an increased amount of nerve in-growth into the annulus and even into the nucleus pulposus. This ingrowth and associated neovascularization have been hypothesized to be associated with increased sensitivity and therefore pain generation in the case of significant DDD. The expression of the neurotrophins such as brain-derived neurotrophic factor (BDNF), the BDNF receptor ‘TrkB’, and Calcitonin Gene Related Peptide (CGRP) plus nerve growth factor have been shown to increase in severely degenerative discs and are thought to promote neural ingrowth into the IVD. Recently we have developed and demonstrated the anti-degenerative effects of a novel, molecular therapy NTG-101 in a large animal model of DDD. PURPOSE To evaluate the expression of the CGRP receptor (CALCRL), BDNF, the BDNF receptor TrkB and the nerve growth factor receptor TrkA in needle puncture injured chondrodystrophic canines treated with saline or NTG-101. STUDY DESIGN/SETTING In vivo laboratory experimentation involving chondrodystrophic canines injured, injected one month later and then assayed 14 weeks post injection PATIENT SAMPLE No human subjects. Animal Care approved study involving chondrodystrophic canines. OUTCOME MEASURES Immunohistochemistry and HALO immunohistochemically stained quantification methods. METHODS We induced DDD using image-guided needle puncture injury of the IVD nucleus pulposus (NP) in 3-yr old chondrodystrophic canines. One month after needle puncture injury the 3 lumbar IVDs/animal were injected (with image guidance) with 350 µl phosphate buffered saline (PBS) or NTG-101. Intervening IVDs were used as no treatment controls. The animals were humanely euthanized 14-weeks post injection, (18-weeks post injury) and IVDs cleaned of extraneous tissues and excessive bone, fixed in 10% buffered formalin, decalcified using Cal-Ex for 6-8 weeks, embedded in paraffin, sectioned at 5µm, mounted on glass slides, stained with relevant antibodies, counterstained with Haematoxylin and cover slipped. Assays consisted of immunohistochemical staining for relevant proteins followed by quantification using cell counting with HALO automated cell-counting scoring (Indica labs). RESULTS We found that in discs injected with NTG-101 relative to PBS injections, there was significantly reduced expression of: CALCRL (Calcitonin Gene Related Peptide receptor) (P CONCLUSIONS We have previously demonstrated that a single injection of NTG-101 markedly inhibits degeneration and confers improved biomechanical properties in a needle puncture injury model of chondrodystrophic canine DDD. Here we further show that the same intervention under identical conditions significantly inhibits the expression of neurotrophins as compared to PBS injections. These results strongly suggest that not only does NTG-101 inhibit the development of DDD but may also inhibit pain associated with such degenerative disc disease. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Bio-Mechanical behaviour of artificial intervertebral disc in lumbar spine

Total Disc replacement has the higher success rate for reducing the lower back pain and increased mobility in intervertebral disc in lumbar spine region. An Artificial disc replacement, the method is designed to bring about pain relief by eliminating the painful disc, then the motion at that spinal section is kept with the use of a prosthetic implant. This creates a need for studies to be conducted to examine these failures. The main aim of this study is to develop and designing an artificial intervertebral lumbar disc based on literature and validates its function using finite element analysis. A finite element model of L4 to L5 section of lumbar spine model was created by using computer tomography scan images of a person. From that a surface model of the L4 to L5 lumbar section model was developed. From that, Different components were added to complete the intact L4-L5 lumbar section model and concerned properties were attributed to each of the component model. This intact spine model was then validated with reported literature. To analyse the range of motion variation and also compared to the validated intact spine analysis results with the reported literature. Thus, a biomechanical behavior study of the lumbar spine was conducted to analyse the range of motion where a semi-constrained artificial lumbar disc is designed and checked for the normal motion by comparing intact model spine and artificial disc implanted spine results using finite element analysis.

The effectiveness of chemonucleolysis with condoliase for treatment of painful lumbar disc herniation

BackgroundChemonucleolysis with condoliase, which degrades chondroitin sulfate, could be a new, minimally invasive therapeutic option for patients with lumbar disc herniation (LDH). The purpose of this study was to analyze prognostic factors for clinical outcomes in LDH patients subjected to chemonucleolysis with condoliase. MethodsInclusion criteria for this procedure were 1) 18–70 years of age; 2) unilateral leg pain and positive straight leg raise (SLR) (<70°) or femoral nerve stretching test; 3) subligamentous extrusion verified on magnetic resonance imaging; 4) neurological symptoms consistent with a compressed nerve root on magnetic resonance imaging (MRI) images; and 5) minimum six months of follow-up. In total, 82 patients (55 men, 27 women; mean age, 47.2 ± 15.5 years; mean follow-up, 9.1 ± 3.0 months) who underwent chemonucleolysis with condoliase for painful LDH were included. An improvement of 50% or more in the Visual analogue scale (VAS) of leg pain was classified as effective. ResultsSeventy patients (85.4%) were classified into the effective (E) group and 12 patients (14.6%) into the less-effective (L) group. Surgical treatment was required in four patients. No severe adverse complications were reported; 41.3% of the patients developed disc degeneration of Pfirrmann grade 1 or more at the injected disc level. Univariate analysis revealed that young age (p = 0.036), without history of epidural or nerve root block (p = 0.024), and injection into the central portion of the intervertebral disc (p = 0.014) were significantly associated with clinical effectiveness. A logistic regression analysis revealed that injection into the central portion of the intervertebral disc (p = 0.049; odds ratio, 4.913; 95% confidence interval, 1.006–26.204) was significantly associated with clinical effectiveness. ConclusionsChemonucleolysis with condoliase is a safe and effective treatment for painful LDH; 85.4% of the patients showed improvement after the treatment without severe adverse events. To obtain the best outcome, condoliase should be injected into the center of the intervertebral disc.

Hypo-Osmotic Loading Induces Expression of IL-6 in Nucleus Pulposus Cells of the Intervertebral Disc Independent of TRPV4 and TRPM7.

Painful intervertebral disc (IVD) degeneration is an age-related process characterized by reduced tissue osmolarity, increased catabolism of the extracellular matrix, and elevated levels of pro-inflammatory molecules. With the aging population and constantly rising treatment costs, it is of utmost importance to identify potential therapeutic targets and new pharmacological treatment strategies for low back pain. Transient receptor potential (TRP) channels are a family of Ca2+ permeable cell membrane receptors, which can be activated by multitude of stimuli and have recently emerged as contributors to joint disease, but were not investigated closer in the IVD. Based on the gene array screening, TRPC1, TRPM7, and TRPV4 were overall the most highly expressed TRP channels in bovine IVD cells. We demonstrated that TRPV4 gene expression was down-regulated in hypo-osmotic condition, whereas its Ca2+ flux increased. No significant differences in Ca2+ flux and gene expression were observed for TRPM7 between hypo- and iso-osmotic groups. Upon hypo-osmotic stimulation, we overall identified via RNA sequencing over 3,000 up- or down-regulated targets, from which we selected aggrecan, ADAMTS9, and IL-6 and investigated whether their altered gene expression is mediated through either the TRPV4 or TRPM7 channel, using specific activators and inhibitors (GSK1016790A/GSK2193874 for TRPV4 and Naltriben/NS8593 for TRPM7). GSK1016790A induced the expression of IL-6 under iso-osmotic condition, alike to hypo-osmotic stimulation alone, indicating that this effect might be TRPV4-mediated. However, using the TRPV4 blocker GSK2193874 failed to prevent the increase of IL-6 under hypo-osmotic condition. A treatment with TRPM7-activator did not cause significant changes in the gene expression of tested targets. In conclusion, while TRPV4 and TRPM7 are likely involved in osmosensing in the IVD, neither of them mediates hypo-osmotically-induced gene expression changes of aggrecan, ADAMTS9, and IL-6.

Hypoxic stress enhances extension and branching of dorsal root ganglion neuronal outgrowth.

It has been shown that painful intervertebral discs (IVDs) were associated with a deeper innervation. However, the effect of the disc's degenerative microenvironment on neuronal outgrowth remains largely unknown. The focus of this study was to determine the influence of hypoxia on dorsal root ganglion (DRG) neurite outgrowth. Toward this aim, the DRG‐derived cell line ND7/23 was either directly subjected to 2% or 20% oxygen conditions or exposed to conditioned medium (CM) collected from IVDs cultured under 2% or 20% oxygen. Viability and outgrowth analysis were performed following 3 days of exposure. Results obtained with the cell line were further validated on cultures of rabbit spinal DRG explants and dissociated DRG neurons. Results showed that hypoxia significantly increased neurite outgrowth length in ND7/23 cells, which was also validated in DRG explant and primary cell culture, although hypoxia conditioned IVD did not significantly increase ND7/23 neurite outgrowth. While hypoxia dramatically decreased the outgrowth frequency in explant cultures, it significantly increased collateral sprouting of dissociated neurons. Importantly, the hypoxia‐induced decrease of outgrowth frequency at the explant level was not due to inhibition of outgrowth branching but rather to neuronal necrosis. In summary, hypoxia in DRG promoted neurite sprouting, while neuronal necrosis may reduce the density of neuronal outgrowth at the tissue level. These findings may help to explain the deeper neo‐innervation found in the painful disc tissue.HighlightsHypoxia promoted elongation and branching of neurite outgrowth at single cell level, but reduced outgrowth density at tissue level, possibly due to hypoxia‐induced neuronal necrosis; these findings may help to explain the deeper neo‐innervation found in clinically painful tissues.

Correlation of Early Outcomes and Intradiscal Interleukin-6 Expression in Lumbar Fusion Patients.

ObjectiveTo determine if there is correlation between intradiscal levels of interleukin-6 (IL-6) and early outcome measures in patients undergoing lumbar fusion for painful disc degeneration. MethodsIntervertebral disc tissue was separated into annulus fibrosus/nucleus pulposus and cultured separately in vitro in serum-free medium (Opti-MEM). Conditioned media was collected after 48 hours. The concentration of IL-6 was quantified using enzyme-linked immunosorbent assay. Pearson correlation coefficients quantified relationships between IL-6 levels and pre- and postoperative visual analogue scale (VAS) back pain and Oswestry Disability Index (ODI), as well as change in VAS/ODI. ResultsSixteen discs were harvested from 9 patients undergoing anterior lumbar interbody fusion (mean age, 47.4 years; range, 21–70 years). Mean preoperative and 6-month postoperative VAS were 8.1 and 3.7, respectively. Mean preoperative and postoperative ODI were 56.2 and 25.6, respectively. There were significant positive correlations between IL-6 expression and postoperative VAS (ρ = 0.38, p = 0.048) and ODI (ρ = 0.44, p = 0.02). No significant correlations were found between intradiscal IL-6 expression and preoperative VAS (ρ = -0.12, p = 0.54). Trends were seen associating IL-6 expression and change in VAS/ODI (ρ = -0.35 p = 0.067; ρ = -0.34, p = 0.08, respectively). A trend associated IL-6 and preoperative ODI (ρ = 0.36, p = 0.063). ConclusionThe direct association between IL-6 expression and VAS/ODI suggests patients with elevated intradiscal cytokine expression may have worse early outcomes than those with lower expression of IL-6 after surgery for symptomatic disc degeneration.

Effect of transcutaneous electrical nerve stimulation on jaw movement-evoked pain in patients with TMJ disc displacement without reduction and healthy controls

Objective: Transcutaneous electrical nerve stimulation (TENS) may serve as non-invasive intervention for painful temporomandibular disorders (TMD) to improve jaw motor function, but its efficacy is still debated. This parallel study evaluated the effect of TENS on pain and movement patterns after repeated jaw movements in patients with painful temporomandibular joints (TMJ) and disc displacement without reduction (DDwoR), and compared with healthy controls.Material and Methods: 20 patients with TMJ pain and DDwoR and 20 age- and gender-matched healthy volunteers were randomly assigned to TENS/sham TENS (sTENS) intervention groups in a block design (10 in each group). Participants performed 20 repeated jaw movements (4 x 5 sessions), and reported pain intensity on a 0–10 Numerical Rating Scale (NRS) subsequently both before and after the intervention. Data were tested by repeated measures analysis of variance (ANOVA).Results: Significant increase of pain intensity and reduction of opening range were shown within repeated jaw movements in TMJ pain patients in contrast to healthy participants (p ≤ .001). Pain was significantly reduced during repeated open-close (p = .007), fast open-close (p = .016) and horizontal movements (p = .023), accompanied with increased opening range (p = .033) and open-close velocity (p = .019) with TENS intervention when compared with sTENS group (p > .05) in TMJ pain patients.Conclusions: This study indicated that movement-evoked pain was reduced either spontaneously or by sTENS in TMJ pain patients with DDwoR, and interestingly, that TENS could attenuate movement-evoked pain and improve jaw motor function during repeated jaw movements. The findings may have implications for TENS treatment in TMJ pain patients with DDwoR.

Combinatorial conditioning of adipose derived-mesenchymal stem cells enhances their neurovascular potential: Implications for intervertebral disc degeneration.

ABSTRACTBackgroundMesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self‐renewal capacity, multilineage potential, and anti‐inflammatory properties. Clinical trials are underway to test the efficacy of stem cell‐based therapies for the repair and regeneration of the degenerate intervertebral disc (IVD), a major cause of back pain. Recently, both bone marrow‐derived MSCs and adipose‐derived stem cells (ASCs) have been assessed for IVD therapy but there is a lack of knowledge surrounding the optimal cell source and the response of transplanted cells to the low oxygen, pro‐inflammatory niche of the degenerate disc. Here, we investigated several neurovascular factors from donor‐matched MSCs and ASCs that may potentiate the survival and persistence of sensory nerve fibers and blood vessels present within painful degenerate discs and their regulation by oxygen tensions and inflammatory cytokines.MethodsDonor‐matched ASCs and MSCs were conditioned with either IL‐1β or TNFα under normoxic (21% O2) or hypoxic (5% O2) conditions. Expression and secretion of several potent neurovascular factors were assessed using qRT‐PCR and human magnetic Luminex assay.ResultsASCs and MSCs expressed constitutive levels of key neurotrophic factors; and stimulation of ASCs with hypoxia triggered increased secretion of both angiogenic factors (Ang‐2 and VEGF‐A) and neurotrophic (NGF and NT‐3) compared to MSCs. We also report increased transcriptional regulation of pain‐associated neuropeptides in hypoxia stimulated ASCs compared to those in normoxic conditions. We demonstrate transcriptional and translational upregulation of NGF, NT‐3, Ang‐1, and FGF‐2 in response to cytokines in ASCs in 21% and 5% O2.ConclusionsThis work highlights fundamental differences between the neurovascular secretome of donor‐matched ASCs and MSCs, demonstrating the importance of cell‐selection for tissue specific regeneration to reduce ectopic sensory nerve and blood vessel survival and improve patient outcomes.

Evaluation of the efficacy of different treatment modalities for painful temporomandibular disorders

The purpose of this study was to clinically evaluate the efficacies of three treatment methods and to compare their outcomes in patients with painful disc displacement. The study group comprised 45 patients with unilateral temporomandibular disorders who fell into Axis I group II (with limited mouth opening) of the Research Diagnostic Criteria for Temporomandibular Disorders. Magnetic resonance imaging was used for definitive diagnosis. The patients were divided randomly into three groups according to the treatment method: splint therapy, splint therapy with ultrasound-guided arthrocentesis, and splint therapy with low-level laser therapy. Patients were followed up after treatment for 6 months. The groups were compared in terms of pain and functional jaw movements (unassisted mouth opening without pain, maximum unassisted mouth opening, and contralateral movements). At the end of treatment, functional jaw movements were significantly increased while pain values were significantly decreased in all groups (P<0.05). Group 2 had a quicker improvement in terms of mouth opening scores at the end of the first month, and unassisted mouth opening without pain was found to be more than 35 millimetres in all groups at the end of 6 months. All treatment modalities showed effective results on pain and functional jaw movements in the treatment of temporomandibular disorders.

250. Interspinous process distraction compared to nonoperative care for moderate lumbar degenerative disc disease: results of the FDA IDE clinical trial

BACKGROUND CONTEXT Interspinous process distraction (IPD) devices aim to alleviate back and leg pain by limiting extension and unloading the 3-joint complex at the affected lumbar level. IPDs may offer a treatment option for painful degenerative disc disease (DDD) that is not yet indicated for fusion or disc replacement. PURPOSE To compare the safety and effectiveness of IPD and nonoperative treatment after 2 years for the treatment of moderate lumbar DDD. STUDY DESIGN/SETTING A prospective, randomized, controlled FDA IDE clinical trial at 23 US centers (ClinicalTrials.gov: NCT00456378). PATIENT SAMPLE A total of 278 patients with moderate low back pain for less than 1 year and radiographic evidence of single-level DDD between L2 and L5 who failed at least 6 weeks but less than 6 months of conservative management were randomized and treated with investigational IPD (n=181) or control nonoperative treatment (n=97). OUTCOME MEASURES The primary endpoint was Overall Success, a composite variable that included: 1) Oswestry Disability Index (ODI) score improvement of ≥ 15 points; and 2) no serious adverse event (AE) caused by the implant or by both the implant and surgical procedure (IPD) or caused by the nonoperative treatment (control); and 3) no secondary surgery (IPD) or treatment surgery (control) at the involved level. Additional safety and effectiveness endpoints included back and leg pain numerical (0-20) rating scales, SF-36 PCS/MCS, AEs and secondary surgeries. METHODS Investigational treatment consisted of the IPD implantation (without decompression) and nonoperative treatments, as necessary. Control treatment consisted of information/ education on low back pain, medication, physical therapy, and epidural and/or facet joint steroidal injections. Clinical and radiographic assessments were performed preoperatively, intra-operatively, and postoperatively up to 2 years. Statistical analyses used Bayesian methods with non-informative priors. Last observation was carried forward (LOCF) for patients lost to follow-up including patients receiving surgery (control crossovers) or additional surgery (IPD investigational) at the involved level. RESULTS Baseline demographic characteristics and outcomes scores were not statistically different between the two groups, except back pain (16.8 for investigational vs 16.1 for control, p=0.033). The IPD rate of Overall Success at 24-months was statistically superior to control (observed rate of 63.0% vs 13.4%, respectively; posterior probability of superiority (pps) > 99.9%). The improvement in outcomes for IPD was statistically superior to control (pps > 99.9%) for: ODI (26.4 vs 1.1), back pain (8.4 vs 1.2), leg pain (4.9 vs -1.1, PCS (12.6 vs.1.4), and MCS (4.4 vs -0.8). Spinous process bony erosion increased slowly to 33.7% (61/181) of patients but was not related to clinical outcomes. Treatment-related serious AEs in the control group were associated with increasing low back pain. Fifteen (8.3%) IPD and 34 (35.1%) control patients experienced a treatment-related serious AE. Twenty (11.0%) IPD patients had secondary surgery and 10 (10.3%) control patients had treatment surgery at the index level. After 6 months of nonoperative treatment, control patients had the option to crossover to IPD: 57 (58.8%) control patients had crossed over by 24 months. CONCLUSIONS These analyses support the superiority of this IPD over conservative care for moderate back pain in appropriately selected patients. FDA DEVICE/DRUG STATUS DIAM™ Spinal Stabilization System (Investigational/Not approved)