Numerical Prediction of the Mechanical Failure of the Intervertebral Disc under Complex Loading Conditions.
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ABSTRACT:
SUBMITTER: Casaroli G
PROVIDER: S-EPMC5344546 | biostudies-other | 2017 Jan
REPOSITORIES: biostudies-other
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Project description:Complex loading develops in multiple spinal motions and in the case of hyperflexion is known to cause intervertebral disc (IVD) injury. Few studies have examined the interacting biologic and structural alterations associated with potentially injurious complex loading, which may be an important contributor to chronic progressive degeneration.This study tested the hypothesis that low magnitudes of axial compression loading applied asymmetrically can induce IVD injury affecting cellular and structural responses in a large animal IVD ex-vivo model.Bovine caudal IVDs were assigned to either a control or wedge group (15°) and placed in organ culture for 7 days under static 0.2MPa load. IVD tissue and cellular responses were assessed through confined compression, qRT-PCR, histology and structural and compositional measurements, including Western blot for aggrecan degradation products.Complex loading via asymmetric compression induced cell death, an increase in caspase-3 staining (apoptosis), a loss of aggrecan and an increase in aggregate modulus in the concave annulus fibrosis. While an up-regulation of MMP-1, ADAMTS4, IL-1?, and IL-6 mRNA, and a reduced aggregate modulus were induced in the convex annulus.Asymmetric compression had direct deleterious effects on both tissue and cells, suggesting an injurious loading regime that could lead to a degenerative cascade, including cell death, the production of inflammatory mediators, and a shift towards catabolism. This explant model is useful to assess how injurious mechanical loading affects the cellular response which may contribute to the progression of degenerative changes in large animal IVDs, and results suggest that interventions should address inflammation, apoptosis, and lamellar integrity.
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Project description:It is difficult to study the breakdown of disc tissue over several years of exposure to bending and lifting by experimental methods. There is also no finite element model that elucidates the failure mechanism due to repetitive loading of the lumbar motion segment. The aim of this study was to refine an already validated poro-elastic finite element model of lumbar motion segment to investigate the initiation and progression of mechanical damage in the disc under simple and complex cyclic loading conditions. Continuum damage mechanics methodology was incorporated into the finite element model to track the damage accumulation in the annulus in response to the repetitive loading. The analyses showed that the damage initiated at the posterior inner annulus adjacent to the endplates and propagated outwards towards its periphery under all loading conditions simulated. The damage accumulated preferentially in the posterior region of the annulus. The analyses also showed that the disc failure is unlikely to happen with repetitive bending in the absence of compressive load. Compressive cyclic loading with low peak load magnitude also did not create the failure of the disc. The finite element model results were consistent with the experimental and clinical observations in terms of the region of failure, magnitude of applied loads and the number of load cycles survived.
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Project description:Human intervertebral disc tissue was obtained from patients (average age 51 yrs) undergoing surgery for lumbar interbody fusion (n=3) or lumbar disc herniation (n=1). Cells were isolated by sequential pronase-collagenase digestion [3]. Cells were passaged twice in monolayer and suspended at a density of 2 x 106 cells/ml in 1.2% alginate (low viscosity, Sigma Chemical, St Louis, MO) dissolved in 150 mM NaCl. Alginate beads were formed by dropwise addition of the alginate from a 22 gauge needle into 102 mM CaCl2, followed by 10 minutes of curing, as described previously [13, 27]. Cell-gel beads were incubated in cell culture media consisting of Ham’s F-12 medium (Gibco BRL, Grand Island, NY), supplemented with 10% FBS (HyClone, Logan, UT), 25 μg/ml ascorbic acid (Sigma, St. Louis, MO), 100 U/ml penicillin, 100 μg/ml streptomycin, and 1 μg/ml Fungizone at 5% CO2 and 37° C. After 24 h, the cell culture medium was removed via pipette and exchanged for one of three osmotically active solutions, representing iso-osmotic, hyper-osmotic and hypo-osmotic media [12, 23, 34]. The iso-osmotic solution consisted of a defined cell culture medium (Ham’s F-12 with supplements as described above; 293 mOsm/kg H2O). The hypo-osmotic solution consisted of the same cell culture media diluted with de-ionized water to a final osmolarity of 250 mOsm/kg H2O. The hyper-osmotic solution consisted of the same cell culture media supplemented with sucrose to a final osmolarity of 450 mOsm/kg H20. The osmolarity of all solution formulations was determined using a freezing-point osmometer (Advanced Laboratory Wide Range 3W2, Advanced Instrument, Needham Heights, MA) as described previously [12]. Cell-alginate beads were cultured for a 4 hour period under one of these conditions, after which the cells were released from alginate in a dissolving buffer (55 mM Na-citrate and 150 mM NaCl), lysed and stored at –80°C. Intervertebral disc (IVD) cells experience a broad range of physical stimuli under physiologic conditions, including alterations in their osmotic environment. In this study, the gene expression profile of human IVD cells was quantified with gene array technology following exposure to varying osmolarity in order to capture the biological responses for a broad set of targets. A total of 42 genes were identified in IVD cells as significantly changed following culture under hyper-osmotic conditions, while a total of 18 genes were identified as significantly changed under hypo-osmotic conditions. Gene expression patterns were verified using RT-PCR. Genes identified in this study include those related to cytoskeleton remodeling and stabilization (ephrin-B2, sarcoglycan beta, IQGAP1), as well as membrane transport (ion transporter SLC21A12, osmolyte tranporter SLC5A3, monocarboxylic acid SLC16A6, and amino acid transporter SLC7A8). An unexpected finding was the differential regulation of the gene for the neurotrophin brain-derived neurotrophic factor by hyper-osmotic stimuli that may be indicative of a physiological response of IVD cells to physical stimuli important in regulating discogenic pain. Keywords = intervertebral disc Keywords = osmotic stimuli Keywords: other
2004-08-07 | GSE1648 | GEO
Project description:The effects of the rib cage on thoracic spine loading are not well studied, but the rib cage may provide stability or share loads with the spine. Intervertebral disc pressure provides insight into spinal loading, but such measurements are lacking in the thoracic spine. Thus, our objective was to examine thoracic intradiscal pressures under applied pure moments, and to determine the effect of the rib cage on these pressures. Human cadaveric thoracic spine specimens were positioned upright in a testing machine, and Dynamic pure moments (0 to ±5?N·m) with a compressive follower load of 400?N were applied in axial rotation, flexion - extension, and lateral bending. Disc pressures were measured at T4-T5 and T8-T9 using needle-mounted pressure transducers, first with the rib cage intact, and again after the rib cage was removed. Changes in pressure vs. moment slopes with rib cage removal were examined. Pressure generally increased with applied moments, and pressure-moment slope increased with rib cage removal at T4-T5 for axial rotation, extension, and lateral bending, and at T8-T9 for axial rotation. The results suggest the intact rib cage carried about 62% and 56% of axial rotation moments about T4-T5 and T8-T9, respectively, as well as 42% of extension moment and 36-43% of lateral bending moment about T4-T5 only. The rib cage likely plays a larger role in supporting moments than compressive loads, and may also play a larger role in the upper thorax than the lower thorax.
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Project description:Mechanical loading has been shown to affect cell viability and matrix maintenance in the intervertebral disc (IVD) but there is no investigation on how cells survive mechanical stress and whether the IVD cells perceive mechanical loading as stress and respond by expression of heat shock proteins. This study investigates the stress response in the IVD in response to compressive loading. Bovine caudal disc organ culture was used to study the effect of physiological range static loading and dynamic loading. Cell activity, gene expression and immunofluorescence staining were used to analyze the cell response. Cell activity and cytoskeleton of the cells did not change significantly after loading. In gene expression analysis, significant up-regulation of heat shock protein-70 (HSP70) was observed in nucleus pulposus after two hours of loading. However, the expression of the matrix remodeling genes did not change significantly after loading. Similarly, expressions of stress response and matrix remodeling genes changed with application and removal of the dynamic loading. The results suggest that stress response was induced by physiological range loading without significantly changing cell activity and upregulating matrix remodeling. This study provides direct evidence on loading induced stress response in IVD cells and contributes to our understanding in the mechanoregulation of intervertebral disc cells.
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Project description:The primary function of the disc is mechanical; therefore, degenerative changes in disc mechanics and the interactions between the annulus fibrosus (AF) and nucleus pulposus (NP) in nondegenerate and degenerate discs are important to functional evaluation. The disc experiences complex loading conditions, including mechanical interactions between the pressurized NP and the surrounding fiber-reinforced AF. Our objective was to noninvasively evaluate the internal deformations of nondegenerate and degenerate human discs under axial compression with flexion, neutral, and extension positions using magnetic resonance imaging and image correlation. The side of applied bending (e.g., anterior AF in flexion) had higher tensile radial and compressive axial strains, and the opposite side of bending exhibited tensile axial strains even though the disc was loaded under axial compression. Degenerated discs exhibited higher compressive axial and tensile radial strains, which suggest that load distribution through the disc subcomponents are altered with degeneration, likely due to the depressurized NP placing more of the applied load directly on the AF. The posterior AF exhibited higher compressive axial and higher tensile radial strains than the other AF regions, and the strains were not correlated with degeneration, suggesting this region undergoes high strains throughout life, which may predispose it to failure and tears. In addition to understanding internal disc mechanics, this study provides important new data into the changes in internal strain with degeneration, data for validation of finite element models, and provides a technique and baseline data for evaluating surgical treatments.
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Project description:[This corrects the article DOI: 10.1371/journal.pone.0161615.].
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Project description:Cells protect themselves from stresses through a cellular stress response. In the interverebral disc, such response was also demonstrated to be induced by various environmental stresses. However, whether compression loading will cause cellular stress response in the nucleus pulposus cells (NPCs) is not well studied. By using an in vitro collagen microencapsulation model, we investigated the effect of compression loading on the stress response of NPCs. Cell viability tests, and gene and protein expression experiments were conducted, with primers for the heat shock response (HSR: HSP70, HSF1, HSP27 and HSP90), and unfolded protein response (UPR: GRP78, GRP94, ATF4 and CHOP) genes and an antibody to HSP72. Different gene expression patterns occurred due to loading type throughout experiments. Increasing the loading strain for a short duration did not increase the stress response genes significantly, but over longer durations, HSP70 and HSP27 were upregulated. Longer loading durations also resulted in a continuous upregulation of HSR genes and downregulation of UPR genes, even after load removal. The rate of apoptosis did not increase significantly after loading, suggesting that stress response genes might play a role in cell survival following mechanical stress. These results demonstrate how mechanical stress might induce and control the expression of HSR and UPR genes in NPCs.
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Project description:Mesenchymal stem cells (MSCs) and scaffolds offer promising perspectives for annulus fibrosus (AF) repair. The repair effect was linked to features of the local mechanical environment related to the differentiation of MSCs. In this study, we established a Fibrinogen-Thrombin-Genipin (Fib-T-G) gel which is sticky and could transfer strain force from AF tissue to the human mesenchymal stem cells (hMSCs) embedded in the gel. After the Fib-T-G biological gel was injected into the AF fissures, the histology scores of intervertebral disc (IVD) and AF tissue showed that Fib-T-G gel could better repair the AF fissure in caudal IVD of rats, and increase the expression of AF-related proteins including Collagen 1 (COL1), Collagen 2 (COL2) as well as mechanotransduction-related proteins including RhoA and ROCK1. To clarify the mechanism that sticky Fib-T-G gel induces the healing of AF fissures and the differentiation of hMSCs, we further investigated the differentiation of hMSCs under mechanical strain in vitro. It was demonstrated that both AF-specific genes, including Mohawk and SOX-9, and ECM markers (COL1, COL2, aggrecan) of hMSCs were up-regulated in the environment of strain force. Moreover, RhoA/ROCK1 proteins were also found to be significantly up-regulated. In addition, we further -demonstrated that the fibrochondroinductive effect of the mechanical microenvironment process could be significantly blocked or up-regulated by inhibiting the RhoA/ROCK1 pathway or overexpressing RhoA in MSCs, respectively. Summarily, this study will provide a therapeutic alternative to repair AF tears and provide evidence that RhoA/ROCK1 is vital for hMSCs response to mechanical strain and AF-like differentiation.
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Project description:Night shift workers with disordered rhythmic mechanical loading are more prone to intervertebral disc degeneration (IDD). Our results showed that circadian rhythm (CR) was dampened in degenerated and aged NP cells. Long-term environmental CR disruption promoted IDD in rats. Excessive mechanical strain disrupted the CR and inhibited the expression of core clock proteins. The inhibitory effect of mechanical loading on the expression of extracellular matrix genes could be reversed by BMAL1 overexpression in NP cells. The Rho/ROCK pathway was demonstrated to mediate the effect of mechanical stimulation on CR. Prolonged mechanical loading for 12 months affected intrinsic CR genes and induced IDD in a model of upright posture in a normal environment. Unexpectedly, mechanical loading further accelerated the IDD in an Light-Dark (LD) cycle-disrupted environment. These results indicated that intrinsic CR disruption might be a mechanism involved in overloading-induced IDD and a potential drug target for night shift workers.
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