Browsing by Subject "Intervertebral Disc"

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    ItemOpen Access
    A magnetic resonance imaging framework for quantifying intervertebral disc deformation in vivo: reliability and application to diurnal variations in lumbar disc shape
    (Journal of biomechanics, 2018-04) DeFrate, LE
    Low back pain is a significant socioeconomic burden in the United States and lumbar intervertebral disc degeneration is frequently implicated as a cause. The discs play an important mechanical role in the spine, yet the relationship between disc function and back pain is poorly defined. The objective of this work was to develop a technique using magnetic resonance imaging (MRI) and three-dimensional modeling to measure in vivo disc deformations. Using this method, we found that disc geometry was measurable with precision less than the in-plane dimensions of a voxel (≈100 µm, 10% of the MRI pixel size). Furthermore, there was excellent agreement between mean disc height, disc perimeter, disc volume and regional disc height measurements for multiple trials from an individual rater (standard deviation <3.1% across all measurements) and between mean height, perimeter, and volume measurements made by two independent raters (error <1.5% across all measurements). We then used this measurement system to track diurnal deformations in the L5-S1 disc in a young, healthy population (n = 8; age 24.1 ± 3.3 yrs; 2 M/6F). We measured decreases in the mean disc height (-8%) and volume (-9%) with no changes in perimeter over an eight-hour workday. We found that the largest height losses occurred in the posterior (-13%) and posterior-lateral (-14%) regions adjacent to the outer annulus fibrosus. Diurnal annulus fibrosus (AF) strains induced by posterior and posterior-lateral height loss may increase the risk for posterior disc herniation or posterior AF tears. These preliminary findings lay a foundation for determining how deviations from normal deformations may contribute to back pain.
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    ItemOpen Access
    Attenuation of inflammatory events in human intervertebral disc cells with a tumor necrosis factor antagonist.
    (Spine, 2011-07) Sinclair, S Michael; Shamji, Mohammed F; Chen, Jun; Jing, Liufang; Richardson, William J; Brown, Christopher R; Fitch, Robert D; Setton, Lori A

    Study design

    The inflammatory responses of primary human intervertebral disc (IVD) cells to tumor necrosis factor α (TNF-α) and an antagonist were evaluated in vitro.

    Objective

    To investigate an ability for soluble TNF receptor type II (sTNFRII) to antagonize TNF-α-induced inflammatory events in primary human IVD cells in vitro.

    Summary of background data

    TNF-α is a known mediator of inflammation and pain associated with radiculopathy and IVD degeneration. sTNFRs and their analogues are of interest for the clinical treatment of these IVD pathologies, although information on the effects of sTNFR on human IVD cells remains unknown.

    Methods

    IVD cells were isolated from surgical tissues procured from 15 patients and cultured with or without 1.4 nmol/L TNF-α (25 ng/mL). Treatment groups were coincubated with varying doses of sTNFRII (12.5-100 nmol/L). Nitric oxide (NO), prostaglandin E₂ (PGE₂), and interleukin-6 (IL6) levels in media were quantified to characterize the inflammatory phenotype of the IVD cells.

    Results

    Across all patients, TNF-α induced large, statistically significant increases in NO, PGE₂, and IL6 secretion from IVD cells compared with controls (60-, 112-, and 4-fold increases, respectively; P < 0.0001). Coincubation of TNF-α with nanomolar doses of sTNFRII significantly attenuated the secretion of NO and PGE₂ in a dose-dependent manner, whereas IL6 levels were unchanged. Mean IC₅₀ values for NO and PGE₂ were found to be 35.1 and 20.5 nmol/L, respectively.

    Conclusion

    Nanomolar concentrations of sTNFRII were able to significantly attenuate the effects of TNF-α on primary human IVD cells in vitro. These results suggest this sTNFR to be a potent TNF antagonist with potential to attenuate inflammation in IVD pathology.
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    ItemOpen Access
    Differential expression of galectin-1 and its interactions with cells and laminins in the intervertebral disc.
    (Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2012-12) Jing, Liufang; So, Stephen; Lim, Shaun W; Richardson, William J; Fitch, Robert D; Setton, Lori A; Chen, Jun
    Galectin-1 (Gal-1), an endogenous β-galactoside-binding protein, binds to laminins, which are highly expressed in the nucleus pulposus (NP) of the intervertebral disc (IVD). The objective of this study is to evaluate the expression of Gal-1 protein in IVD tissues during aging and the effect of Gal-1 on IVD cell adhesion to laminins. Tissues from rat, porcine, and human (scoliosis or disc degeneration) IVDs were used to evaluate Gal-1 expression via immunostaining, RT-PCR, and Western blot analysis. Attachment of isolated IVD cells (porcine and human) on select laminin isoforms (LM-111 and LM-511) was compared with/without pre-incubation with exogenous Gal-1. A biotinylated Gal-1(B-Gal-1) was used to evaluate for binding to IVD cells and to select for IVD cells by magnetic activated cell sorting (MACS). NP cells expressed high levels of Gal-1 protein as compared to anulus fibrosus (AF) cells in immature tissues, while exogenous Gal-1 increased both NP and AF cell attachment to laminins and exhibited a similar binding to both cell types in vitro. With aging, Gal-1 levels in NP tissue appeared to decrease. In addition, incubation with B-Gal-1 was able to promote the retention of more than 50% of IVD cells via MACS. Our results provide new findings for the presence and functional role of Gal-1 within IVDs. Similar staining patterns for Gal-1 and LM-511 in IVD tissue suggest that Gal-1 may serve as an adhesion molecule to interact with both cells and laminins. This MACS protocol may be useful for selecting pure IVD cells from mixed cells of pathological tissue.
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    ItemOpen Access
    Does smoking have an impact on fusion rate in single-level anterior cervical discectomy and fusion with allograft and rigid plate fixation? Clinical article.
    (Journal of neurosurgery. Spine, 2013-11) Luszczyk, Myles; Smith, Justin S; Fischgrund, Jeffrey S; Ludwig, Steven C; Sasso, Rick C; Shaffrey, Christopher I; Vaccaro, Alexander R

    Object

    Although smoking has been shown to negatively affect fusion rates in patients undergoing multilevel fusions of the cervical and lumbar spine, the effect of smoking on fusion rates in patients undergoing single-level anterior cervical discectomy and fusion (ACDF) with allograft and plate fixation has yet to be thoroughly investigated. The objective of the present study was to address the effect of smoking on fusion rates in patients undergoing a 1-level ACDF with allograft and a locked anterior cervical plate.

    Methods

    This study is composed of patients from the control groups of 5 separate studies evaluating the use of an anterior cervical disc replacement to treat cervical radiculopathy. For each of the 5 studies the control group consisted of patients who underwent a 1-level ACDF with allograft and a locked cervical plate. The authors of the present study reviewed data obtained in a total of 573 patients; 156 patients were smokers and 417 were nonsmokers. A minimum follow-up period of 24 months was required for inclusion in this study. Fusion status was assessed by independent observers using lateral, neutral, and flexion/extension radiographs.

    Results

    An overall fusion rate of 91.4% was achieved in all 573 patients. A solid fusion was shown in 382 patients (91.6%) who were nonsmokers. Among patients who were smokers, 142 (91.0%) had radiographic evidence of a solid fusion. A 2-tailed Fisher exact test revealed a p value of 0.867, indicating no difference in the union rates between smokers and nonsmokers.

    Conclusions

    The authors found no statistically significant difference in fusion status between smokers and nonsmokers who underwent a single-level ACDF with allograft and a locked anterior cervical plate. Although the authors do not promote tobacco use, it appears that the use of allograft with a locked cervical plate in single-level ACDF among smokers produces similar fusion rates as it does in their nonsmoking counterparts.
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    ItemOpen Access
    Frequency, risk factors, and treatment of distal adjacent segment pathology after long thoracolumbar fusion: a systematic review.
    (Spine, 2012-10) Kasliwal, Manish K; Shaffrey, Christopher I; Lenke, Lawrence G; Dettori, Joseph R; Ely, Claire G; Smith, Justin S

    Study design

    Systematic review.

    Objective

    To systematically review the literature related to distal adjacent segment pathology (ASP) after long thoracolumbar fusions for deformity including frequency, risk factors, frequency differences between adolescents and adults, surgical approach for revision, and revision complications.

    Summary of background data

    Spinal deformity surgery complications include ASP. Although ASP at the rostral end of instrumented fusions has been well described, substantially less has been documented about distal ASP.

    Methods

    A systematic search was conducted in Medline and the Cochrane Collaboration Library for articles published between January 1, 1983, and March 15, 2012. We included all articles that described distal ASP after long thoracolumbar fusion for deformity. Radiographical ASP (RASP) was defined as evidence of ASP based on imaging, and clinical ASP (CASP) was defined as symptomatic ASP.

    Results

    Seven retrospective cohort studies met inclusion criteria. Distal CASP developed in 17.7% at 2- 6-year follow-up and 19.8% at 9-year follow-up, whereas reoperation due to CASP was reported in 15.6% at 2 to 6 years and 14.4% at 9 years. Distal RASP was more frequent (44.7%-65.5%). Preoperative sagittal imbalance was associated with increased risk of distal ASP. There was increased risk of CASP in patients with higher postoperative fractional curve and increased risk of RASP in younger patients and those with preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5-S1 disc space narrowing. No studies meeting inclusion criteria compared distal ASP in adults and adolescents or defined the best approach or complications for distal ASP revision.

    Conclusion

    Low-quality evidence suggests a cumulative rate of 18% to 20% for CASP and 45% to 65% for RASP after long thoracolumbar fusion for spinal deformity during 9-year follow-up. Low-quality evidence suggests an association between preoperative sagittal imbalance and distal ASP, with greater risk of distal ASP in patients with sagittal imbalance. Low-quality evidence suggests increased risk of CASP in patients with higher postoperative fractional curve and increased risk of RASP in younger patients and those with preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5-S1 disc space narrowing.

    Consensus statement

    1. The risk of developing new symptoms secondary to distal adjacent segment pathology following long thoracolumbar fusion for deformity is approximately 18–20% during a period of 9 years follow up, and most of these patients will require revision surgery. Strength of Statement: Weak. 2. The risk of developing distal adjacent segment pathology may be higher in those with preoperative sagittal imbalance, preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5–S1 disc space narrowing. Strength of Statement: Weak.
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    ItemOpen Access
    Injectable laminin-functionalized hydrogel for nucleus pulposus regeneration.
    (Biomaterials, 2013-10) Francisco, Aubrey T; Mancino, Robert J; Bowles, Robby D; Brunger, Jonathan M; Tainter, David M; Chen, Yi-Te; Richardson, William J; Guilak, Farshid; Setton, Lori A
    Cell delivery to the pathological intervertebral disc (IVD) has significant therapeutic potential for enhancing IVD regeneration. The development of injectable biomaterials that retain delivered cells, promote cell survival, and maintain or promote an NP cell phenotype in vivo remains a significant challenge. Previous studies have demonstrated NP cell - laminin interactions in the nucleus pulposus (NP) region of the IVD that promote cell attachment and biosynthesis. These findings suggest that incorporating laminin ligands into carriers for cell delivery may be beneficial for promoting NP cell survival and phenotype. Here, an injectable, laminin-111 functionalized poly(ethylene glycol) (PEG-LM111) hydrogel was developed as a biomaterial carrier for cell delivery to the IVD. We evaluated the mechanical properties of the PEG-LM111 hydrogel, and its ability to retain delivered cells in the IVD space. Gelation occurred in approximately 20 min without an initiator, with dynamic shear moduli in the range of 0.9-1.4 kPa. Primary NP cell retention in cultured IVD explants was significantly higher over 14 days when cells were delivered within a PEG-LM111 carrier, as compared to cells in liquid suspension. Together, these results suggest this injectable laminin-functionalized biomaterial may be an easy to use carrier for delivering cells to the IVD.
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    ItemOpen Access
    Integrin-mediated interactions with extracellular matrix proteins for nucleus pulposus cells of the human intervertebral disc.
    (J Orthop Res, 2013-10) Bridgen, DT; Gilchrist, CL; Richardson, WJ; Isaacs, RE; Brown, CR; Yang, KL; Chen, J; Setton, LA
    The extracellular matrix (ECM) of the human intervertebral disc is rich in molecules that interact with cells through integrin-mediated attachments. Porcine nucleus pulposus (NP) cells have been shown to interact with laminin (LM) isoforms LM-111 and LM-511 through select integrins that regulate biosynthesis and cell attachment. Since human NP cells lose many phenotypic characteristics with age, attachment and interaction with the ECM may be altered. Expression of LM-binding integrins was quantified for human NP cells using flow cytometry. The cell-ECM attachment mechanism was determined by quantifying cell attachment to LM-111, LM-511, or type II collagen after functionally blocking specific integrin subunits. Human NP cells express integrins β1, α3, and α5, with over 70% of cells positive for each subunit. Blocking subunit β1 inhibited NP cell attachment to all substrates. Blocking subunits α1, α2, α3, and α5 simultaneously, but not individually, inhibits NP cell attachment to laminins. While integrin α6β1 mediated porcine NP cell attachment to LM-111, we found integrins α3, α5, and β1 instead contributed to human NP cell attachment. These findings identify integrin subunits that may mediate interactions with the ECM for human NP cells and could be used to promote cell attachment, survival, and biosynthesis in cell-based therapeutics.
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    ItemOpen Access
    Interleukin-17 synergizes with IFNγ or TNFα to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells.
    (Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2011-01) Gabr, Mostafa A; Jing, Liufang; Helbling, Antonia R; Sinclair, S Michael; Allen, Kyle D; Shamji, Mohammed F; Richardson, William J; Fitch, Robert D; Setton, Lori A; Chen, Jun
    Interleukin-17 (IL-17) is a cytokine recently shown to be elevated, along with interferon-γ (IFNγ) and tumor necrosis factor (TNFα), in degenerated and herniated intervertebral disc (IVD) tissues, suggesting a role for these cytokines in intervertebral disc disease. The objective of our study was to investigate the involvement of IL-17 and costimulants IFNγ and TNFα in intervertebral disc pathology. Cells were isolated from anulus fibrosus and nucleus pulposus tissues of patients undergoing surgery for intervertebral disc degeneration or scoliosis. The production of inflammatory mediators, nitric oxide (NOx), prostaglandin E2 (PGE2) and interleukin-6 (IL-6), as well as intercellular adhesion molecule (ICAM-1) expression, were quantified for cultured cells following exposure to IL-17, IFNγ, and TNFα. Intervertebral disc cells exposed to IL-17, IFNγ, or TNFα showed a remarkable increase in inflammatory mediator release and ICAM-1 expression (GLM and ANOVA, p < 0.05). Addition of IFNγ or TNFα to IL-17 demonstrated a synergistic increase in inflammatory mediator release, and a marked increase in ICAM-1 expression. These findings suggest that IVD cells not only respond with a catabolic phenotype to IL-17 and costimulants IFNγ and TNFα, but also express surface ligands with consequent potential to recruit additional lymphocytes and immune cells to the IVD microenvironment. IL-17 may be an important regulator of inflammation in the IVD pathologies.
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    ItemOpen Access
    Lumbar intervertebral disc diurnal deformations and T2 and T1rho relaxation times vary by spinal level and disc region.
    (European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 2022-03) Martin, John T; Oldweiler, Alexander B; Kosinski, Andrzej S; Spritzer, Charles E; Soher, Brian J; Erickson, Melissa M; Goode, Adam P; DeFrate, Louis E

    Purpose

    Magnetic resonance imaging (MRI) is routinely used to evaluate spine pathology; however, standard imaging findings weakly correlate to low back pain. Abnormal disc mechanical function is implicated as a cause of back pain but is not assessed using standard clinical MRI. Our objective was to utilize our established MRI protocol for measuring disc function to quantify disc mechanical function in a healthy cohort.

    Methods

    We recruited young, asymptomatic volunteers (6 male/6 female; age 18-30 years; BMI < 30) and used MRI to determine how diurnal deformations in disc height, volume, and perimeter were affected by spinal level, disc region, MRI biomarkers of disc health (T2, T1rho), and Pfirrmann grade.

    Results

    Lumbar discs deformed by a mean of -6.1% (95% CI: -7.6%, -4.7%) to -8.0% (CI: -10.6%, -5.4%) in height and -5.4% (CI: -7.6%, -3.3%) to -8.5% (CI: -11.0%, -6.0%) in volume from AM to PM across spinal levels. Regional deformations were more uniform in cranial lumbar levels and concentrated posteriorly in the caudal levels, reaching a maximum of 13.1% at L5-S1 (CI:-16.1%, -10.2%). T2 and T1rho relaxation times were greatest in the nucleus and varied circumferentially within the annulus. T2 relaxation times were greatest at the most cranial spinal levels and decreased caudally. In this young healthy cohort, we identified a weak association between nucleus T2 and the diurnal change in the perimeter.

    Conclusions

    Spinal level is a key factor in determining regional disc deformations. Interestingly, deformations were concentrated in the posterior regions of caudal discs where disc herniation is most prevalent.
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    ItemOpen Access
    Measurement of intracellular strain on deformable substrates with texture correlation.
    (J Biomech, 2007) Gilchrist, Christopher L; Witvoet-Braam, Sietske W; Guilak, Farshid; Setton, Lori A
    Mechanical stimuli are important factors that regulate cell proliferation, survival, metabolism and motility in a variety of cell types. The relationship between mechanical deformation of the extracellular matrix and intracellular deformation of cellular sub-regions and organelles has not been fully elucidated, but may provide new insight into the mechanisms involved in transducing mechanical stimuli to biological responses. In this study, a novel fluorescence microscopy and image analysis method was applied to examine the hypothesis that mechanical strains are fully transferred from a planar, deformable substrate to cytoplasmic and intranuclear regions within attached cells. Intracellular strains were measured in cells derived from the anulus fibrosus of the intervertebral disc when attached to an elastic silicone membrane that was subjected to tensile stretch. Measurements indicated cytoplasmic strains were similar to those of the underlying substrate, with a strain transfer ratio (STR) of 0.79. In contrast, nuclear strains were much smaller than those of the substrate, with an STR of 0.17. These findings are consistent with previous studies indicating nuclear stiffness is significantly greater than cytoplasmic stiffness, as measured using other methods. This study provides a novel method for the study of cellular mechanics, including a new technique for measuring intranuclear deformations, with evidence of differential magnitudes and patterns of strain transferred from the substrate to cell cytoplasm and nucleus.
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    ItemOpen Access
    The role of extracellular matrix elasticity and composition in regulating the nucleus pulposus cell phenotype in the intervertebral disc: a narrative review.
    (J Biomech Eng, 2014-02) Hwang, Priscilla Y; Chen, Jun; Jing, Liufang; Hoffman, Brenton D; Setton, Lori A
    Intervertebral disc (IVD) disorders are a major contributor to disability and societal health care costs. Nucleus pulposus (NP) cells of the IVD exhibit changes in both phenotype and morphology with aging-related IVD degeneration that may impact the onset and progression of IVD pathology. Studies have demonstrated that immature NP cell interactions with their extracellular matrix (ECM) may be key regulators of cellular phenotype, metabolism and morphology. The objective of this article is to review our recent experience with studies of NP cell-ECM interactions that reveal how ECM cues can be manipulated to promote an immature NP cell phenotype and morphology. Findings demonstrate the importance of a soft (<700 Pa), laminin-containing ECM in regulating healthy, immature NP cells. Knowledge of NP cell-ECM interactions can be used for development of tissue engineering or cell delivery strategies to treat IVD-related disorders.