Advanced Strategies for the Regeneration of Lumbar Disc Annulus Fibrosus.

Damage to the annulus fibrosus (AF), the outer region of the intervertebral disc (IVD), results in an undesirable condition that may accelerate IVD degeneration causing low back pain. Despite intense research interest, attempts to regenerate the IVD have failed so far and no effective strategy has translated into a successful clinical outcome. Of particular significance, the failure of strategies to repair the AF has been a major drawback in the regeneration of IVD and nucleus replacement. It is unlikely to secure regenerative mediators (cells, genes, and biomolecules) and artificial nucleus materials after injection with an unsealed AF, as IVD is exposed to significant load and large deformation during daily activities. The AF defects strongly change the mechanical properties of the IVD and activate catabolic routes that are responsible for accelerating IVD degeneration. Therefore, there is a strong need to develop effective therapeutic strategies to prevent or reconstruct AF damage to support operational IVD regenerative strategies and nucleus replacement. By the way of this review, repair and regenerative strategies for AF reconstruction, their current status, challenges ahead, and future outlooks were discussed

Bony Stress and Its Association With Intervertebral Disc Degeneration in the Lumbar Spine: A Systematic Review of Clinical and Basic Science Studies.

STUDY DESIGN: Translational review encompassing basic science and clinical evidence. OBJECTIVES: Multiple components of the lumbar spine interact during its normal and pathological function. Bony stress in the lumbar spine is recognized as a factor in the development of pars interarticularis defect and stress fractures, but its relationship with intervertebral disc (IVD) degeneration is not well understood. Therefore, we conducted a systematic review to examine the relationship between bony stress and IVD degeneration. METHODS: Online databases Scopus, PubMed and MEDLINE via OVID were searched for relevant studies published between January 1980-February 2020, using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Two authors independently analyzed the data, noting characteristics and biases in various studies. RESULTS: Thirty-two articles were included in the review: 8 clinical studies, 9 finite element modeling studies, 3 in-vivo biomechanical testing studies, and 12 in-vitro biomechanical testing studies. Of the 32 articles, 19 supported, 4 rejected and 9 made no conclusion on the hypothesis that there is a positive associative relationship between IVD degeneration and bony stress. However, sufficient evidence was not available to confirm or reject a causal relationship. CONCLUSIONS: Most studies suggest that the prevalence of IVD degeneration increases in the presence of bony stress; whether a causal relationship exists is unclear. The literature recommends early diagnosis and clinical suspicion of IVD degeneration and bony stress. Longitudinal studies are required to explore causal relationships between IVD degeneration and bony stress

Is Stand-Alone Anterior Lumbar Interbody Fusion a Safe and Efficacious Treatment for Isthmic Spondylolisthesis of L5-S1?

STUDY DESIGN: A systematic review. OBJECTIVE: The objective of this study was to determine the safety and efficacy of stand-alone anterior lumbar interbody fusion (sa-ALIF) for the treatment of symptomatic isthmic spondylolisthesis of L5-S1 by assessing the level of available clinical and radiographic evidence. METHODS: A systematic review utilizing Medline, Embase, and Scopus online databases was undertaken. Clinical, radiographic, and adverse outcome data were extracted for the relevant isthmic spondylolisthesis cases with the intention of undertaking a meta-analysis. RESULTS: The database search between January 1980 and December 2015 yielded 23 articles that concerned sa-ALIF for isthmic spondylolisthesis of L5-S1. Only in 9 of the 23 articles data could be extracted specific to sa-ALIF for isthmic spondylolisthesis of L5-S1. There was considerable inconsistency in the standards for reporting outcomes of the surgery due to which meta-analysis could not be undertaken, and hence each article was reviewed. CONCLUSIONS: There was insufficient evidence to support the safety and efficacy of sa-ALIF for the treatment of isthmic spondylolisthesis of L5-S1. Although sa-ALIF is widely documented in the literature, there was insufficient evidence to support its use in treating this specific pathology. The unique pathological and anatomical situation that isthmic spondylolisthesis of L5-S1 presents must be recognized and its treatment with sa-ALIF should be well thought out

Elastic fibers: The missing key to improve engineering concepts for reconstruction of the Nucleus Pulposus in the intervertebral disc.

The increasing prevalence of low back pain has imposed a heavy economic burden on global healthcare systems. Intense research activities have been performed for the regeneration of the Nucleus Pulposus (NP) of the IVD; however, tissue-engineered scaffolds have failed to capture the multi-scale structural hierarchy of the native tissue. The current study revealed for the first time, that elastic fibers form a network across the NP consisting of straight and thick parallel fibers that were interconnected by wavy fine fibers and strands. Both straight fibers and twisted strands were regularly merged or branched to form a fine elastic network across the NP. As a key structural feature, ultrathin (53 ± 7 nm), thin (215 ± 20 nm), and thick (890 ± 12 nm) elastic fibers were observed in the NP. While our quantitative analysis for measurement of the thickness of elastic fibers revealed no significant differences (p < 0.633), the preferential orientation of fibers was found to be significantly different (p < 0.001) across the NP. The distribution of orientation for the elastic fibers in the NP represented one major organized angle of orientation except for the central NP. We found that the distribution of elastic fibers in the central NP was different from those located in the peripheral regions representing two symmetrically organized major peaks (±45⁰). No significant differences in the maximum fiber count at the major angles of orientation (±45⁰) were observed for both peripheral (p = 0.427) and central NP (p = 0.788). Based on these new findings a structural model for the elastic fibers in the NP was proposed. The geometrical presentation, along with the distribution of elastic fibers orientation, resulting from the present study identifies the ultrastructural organization of elastic fibers in the NP important towards understanding their mechanical role which is still under investigation. Given the results of this new geometrical analysis, more-accurate multiscale finite element models can now be developed, which will provide new insights into the mechanobiology of the IVD. In addition, the results of this study can potentially be used for the fabrication of bio-inspired tissue-engineered scaffolds and IVD models to truly capture the multi-scale structural hierarchy of IVDs. STATEMENT OF SIGNIFICANCE: Visualization of elastic fibers in the nucleus of the intervertebral disk under high magnification was not reported before. The present research utilized extracellular matrix partial digestion to address significant gaps in understanding of nucleus microstructure that can potentially be used for the fabrication of bio-inspired tissue-engineered scaffolds and disk models to truly capture the multi-scale structural hierarchy of discs

Measuring compressive loads on a 'smart' lumbar interbody fusion cage: Proof of concept.

There are several complications associated with lumbar interbody fusion surgery however, pseudarthrosis (non-union) presents a multifaceted challenge in the postoperative management of the patient. Rates of pseudarthrosis range from 3 to 20 % in patients with healthy bone and 20 to 30 % in patients with osteoporosis. The current methods in post-operative follow-up - radiographs and CT, have high false positive rates and poor agreement between them. The aim of this study was to develop and test a proof-of-concept load-sensing interbody cage that may be used to monitor fusion progression. Piezoresistive pressure sensors were calibrated and embedded within a polyether ether ketone (PEEK) interbody cage. Silicone and poly (methyl methacrylate) (PMMA) were inserted in the graft regions to simulate early and solid fusion. The load-sensing cage was subjected to distributed and eccentric compressive loads up to 900 N between synthetic lumbar vertebral bodies. Under maximum load, the anterior sensors recorded a 56-58 % reduction in pressure in the full fusion state compared to early fusion. Lateral regions measured a 36-37 % stress reduction while the central location reduced by 45 %. The two graft states were distinguishable by sensor-recorded pressure at lower loads. The sensors more effectively detected left and right eccentric loads compared to anterior and posterior. Further, the load-sensing cage was able to detect changes in endplate stiffness. The proof-of-concept 'smart' cage could detect differences in fusion state, endplate stiffness, and loading conditions in this in vitro experimental setup

Mild (not severe) disc degeneration is implicated in the progression of bilateral L5 spondylolysis to spondylolisthesis

© 2018 The Author(s). Background: Spondylolytic (or lytic) spondylolisthesis is often associated with disc degeneration at the index-level; however, it is not clear if disc degeneration is the cause or the consequence of lytic spondylolisthesis. The main objective of this computed tomography based finite element modelling study was to examine the role of different grades of disc degeneration in the progression of a bilateral L5-lytic defect to spondylolisthesis. Methods: High-resolution computed tomography data of the lumbosacral spine from an anonymised healthy male subject (26 years old) were segmented to build a 3D-computational model of an INTACT L1-S1 spine. The INTACT model was manipulated to generate four more models representing a bilateral L5-lytic defect and the following states of the L5-S1 disc: nil degeneration (NOR LYTIC), mild degeneration (M-DEG LYTIC), mild degeneration with 50% disc height collapse (M-DEG-COL LYTIC), and severe degeneration with 50% disc height collapse(S-COL LYTIC). The models were imported into a finite element modelling software for pre-processing, running nonlinear-static solves, and post-processing of the results. Results: Compared with the baseline INTACT model, M-DEG LYTIC model experienced the greatest increase in kinematics (Fx range of motion: 73% ↑, Fx intervertebral translation: 53%↑), shear stresses in the annulus (Fx anteroposterior: 163%↑, Fx posteroanterior: 31%↑), and strain in the iliolumbar ligament (Fx: 90%↑). The S-COL LYTIC model experienced a decrease in mobility (Fx range of motion: 48%↓, Fx intervertebral translation: 69%↓) and an increase in normal stresses in the annulus (Fx Tensile: 170%↑; Fx Compressive: 397%↑). No significant difference in results was noted between M-DEG-COL LYTIC and S-COL LYTIC models. Conclusions: In the presence of a bilateral L5 spondylolytic defect, a mildly degenerate index-level disc experienced greater intervertebral motions and shear stresses compared with a severely degenerate index-level disc in flexion and extension bending motions. Disc height collapse, with or without degenerative changes in the stiffness properties of the disc, is one of the plausible re-stabilisation mechanisms available to the L5-S1 motion segment to mitigate increased intervertebral motions and shear stresses due to a bilateral L5 lytic defect

The Role of Sacral Slope in the Progression of a Bilateral Spondylolytic Defect at L5 to Spondylolisthesis: A Biomechanical Investigation Using Finite Element Analysis

© The Author(s) 2017. Study Design: A biomechanical study using finite element analysis. Objectives: The main objective of this study was to investigate the role of sacral slope in the progression of a L5 bilateral spondylolytic defect to spondylolisthesis. Methods: A 3-dimensional model of lumbosacral spine was built using computed tomography (CT) data procured from an anonymized healthy male subject. The segmented CT data was manipulated to generate 3 more models representing L5 bilateral spondylolytic defect with normal sacral slope (SS), sacral slope increased by 10° (SS+10), and sacral slope decreased by 10° (SS-10). The 3D models were imported into finite element modelling software Strand7 for preprocessing, running nonlinear static solves, and postprocessing of the results. Results: Directional biomechanical instabilities were induced in the lumbosacral spine as a result of changes in the L5-S1 disc shape secondary to the changes in sacral slope. Compared with the normal L5 lytic model, wedging of the L5-S1 disc (SS+10) resulted in a significantly greater range of motion in flexion (18% ↑) but extension motion characteristics were similar. Conversely, flattening of the L5-S1 disc (SS-10) resulted in a significantly greater range of motion in extension (16% ↑) but flexion motion characteristics were similar to that of the normal L5 lytic model. Conclusions: Variations in sacral slope while preserving the L5-S1 mid-disc height and orientation of the L5 vertebra resulted in variations in the L5-S1 disc shape. The results suggest that for such extremities in the L5-S1 disc shape different pathomechanisms exist for the progression of the L5 lytic defect to spondylolisthesis

A novel magnetic resonance imaging postprocessing technique for the assessment of intervertebral disc degeneration-Correlation with histological grading in a rabbit disc degeneration model.

Introduction: Estimation of intervertebral disc degeneration on magnetic resonance imaging (MRI) is challenging. Qualitative schemes used in clinical practice correlate poorly with pain and quantitative techniques have not entered widespread clinical use. Methods: As part of a prior study, 25 New Zealand white rabbits underwent annular puncture to induce disc degeneration in 50 noncontiguous lumbar discs. At 16 weeks, the animals underwent multi-echo T2 MRI scanning and were euthanized. The discs were stained and examined histologically. Quantitative T2 relaxation maps were prepared using the nonlinear least squares method. Decay Variance maps were created using a novel technique of aggregating the deviation in the intensity of each echo signal from the expected intensity based on the previous rate of decay. Results: Decay Variance maps showed a clear and well demarcated nucleus pulposus with a consistent rate of decay (low Decay Variance) in healthy discs that showed progressively more variable decay (higher Decay Variance) with increasing degeneration. Decay Variance maps required significantly less time to generate (1.0 ± 0.0 second) compared with traditional T2 relaxometry maps (5 (±0.9) to 1788.9 (±116) seconds). Histology scores correlated strongly with Decay Variance scores (r = 0.82, P < .01) and weakly with T2 signal intensity (r = 0.32, P < .01) and quantitative T2 relaxometry (r = 0.39, P < .01). Decay Variance had superior sensitivity and specificity for the detection of degenerate discs when compared to T2 signal intensity or Quantitative T2 mapping. Conclusion: Our results show that using a multi-echo T2 MRI sequence, Decay Variance can quantitatively assess disc degeneration more accurately and with less image-processing time than quantitative T2 relaxometry in a rabbit disc puncture model. The technique is a viable candidate for quantitative assessment of disc degeneration on MRI scans. Further validation on human subjects is needed

Pathophysiological Correlation between Cigarette Smoking and Amyotrophic Lateral Sclerosis

Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic differentiation of mesenchymal stem cells, but its effect on NP cells remains largely unknown. Our aim was to investigate GDF6 signalling in adult human NP cells derived from degenerate tissue and determine the signal transduction pathways critical for GDF6-mediated phenotypic changes and tissue homeostatic mechanisms. This study demonstrates maintained expression of GDF6 receptors in human NP and annulus fibrosus (AF) cells across a range of degeneration grades at gene and protein level. We observed an anabolic response in NP cells treated with recombinant GDF6 (increased expression of matrix and NP-phenotypic markers; increased glycosaminoglycan production; no change in catabolic enzyme expression), and identified the signalling pathways involved in these responses (SMAD1/5/8 and ERK1/2 phosphorylation, validated by blocking studies). These findings suggest that GDF6 promotes a healthy disc tissue phenotype in degenerate NP cells through SMAD-dependent and -independent (ERK1/2) mechanisms, which is important for development of GDF6 therapeutic strategies for treatment of degenerate discs.</jats:p