Modic changes in the lumbar vertebral column of chondrodystrophic and non-chondrodystrophic dogs with intervertebral disc disease.

Introduction: Modic changes (MC) are signs of vertebral pathology visible on magnetic resonance (MR) images that have been associated with low back pain (LBP) and disc degeneration in people. Multiple breeds of dogs also develop MCs and coincident back pain. However, the association between breed, MC, and spinal pathologies has yet to be fully elucidated. This study aimed to identify the prevalence of MC that occur spontaneously in the lumbar vertebral column of dogs diagnosed with intervertebral disc disease (IVDD) and examine their association with demographic criteria and the disc width index (DWI). Methods: Medical records and lumbar vertebral column MR images were examined from 104 dogs (831 intervertebral disc spaces and adjacent vertebrae), which were divided into three groups: chondrodystrophic dogs (CD; n =54) and non-chondrodystrophic dogs (NCD; n =30) with IVDD as the primary diagnosis, and control dogs (n =20) with other spinal diseases as their primary diagnosis. Results: Increasing age and a diagnosis of IVDD were significantly associated with MC in dogs (p < 0.001 and p = 0.0062, respectively). In CD dogs with IVDD, Type 2 MC were most prevalent, whereas, in NCD dogs, Type 3 MC were the most prevalent type. Type 2 MC were distributed nearly equally across the lumbar vertebral column, while Type 3 MC were primarily detected at the level of L7-S1. Discussion: This study demonstrated that MC developed spontaneously in dogs, are common in dogs diagnosed with IVDD, and the type observed varies by breed. Further research is needed to understand the pathogenesis of MC; however, the increased presence of Type 2 MC in CD dogs, similar to what is found in people with disc degeneration, suggests that CD dogs could serve as models for MC in people.

Potential Use of Extracellular Vesicles in the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, and several studies have evaluated the efficacy of extracellular vesicles (EVs) in the treatment of IVDD. The databases PubMed, Embase, and Cochrane Library were systematically searched from inception to the end of 2022 to identify studies investigating the therapeutic potential of cell-derived EVs for IVDD treatment. The following outcome measures were utilized: magnetic resonance imaging (MRI) Pfirrmann grading system, disc height index (DHI), histological grading, and apoptosis rate. A comprehensive meta-analysis was conducted, including a total of 13 articles comprising 19 studies involving 218 experimental animals. Comparative analysis between normal cell-derived EVs and placebo revealed significant reductions in MRI grade, increased DHI values, decreased nucleus pulposus cell apoptosis rates, and improved tissue grades. These findings collectively demonstrate the effective inhibition of IVDD through the application of EVs derived from cells. In conclusion, this study provides an updated synthesis of evidence supporting the efficacy of EVs as a promising therapeutic approach for IVDD treatment.

Is Intervertebral Disc Degeneration a Compensatory Mechanism in Adult Tethered Cord Syndrome?

OBJECTIVE: The purpose of the present study was to evaluate the influence of high nerve tension on lumbar disc degeneration and sagittal morphologies. MATERIALS AND METHODS: A total of 50 young and middle-aged patients (mean age 32.1 ± 7.4 years, 22 men and 28 women) who suffered from tethered cord syndrome (TCS) were retrospectively assessed by two observers. Demographic and radiological data were recorded, including lumbar disc degeneration, disc height index and lumbar spine angle, and were compared with 50 patients (mean age 29.7 ± 5.4 years, 22 men and 28 women) without spinal cord abnormalities. Statistical associations were assessed by student's t-test and chi-square test. RESULTS: Our results showed patients with TCS had a significantly higher rate of lumbar disc degeneration in L1/2, L2/3, L4/5 and L5/S1 than in those without TCS (P < 0.05). Moreover, the rates of multilevel disc degeneration and severe disc degeneration in TCS group were significantly higher than those in control group (P < 0.01). The mean disc height index of L3/4 and L4/5 in TCS group was significantly lower than that in control group (P < 0.05). The mean lumbosacral angle of TCS patients was significantly higher than that of patients without TCS (38.4 ± 3.5°vs. 33.7 ± 5.9°, P < 0.01). CONCLUSIONS: We found a certain correlation between TCS and lumbar disc degeneration and lumbosacral angle enlargement, suggesting that the spine reduces the high tension of the spinal cord through disc degeneration. Therefore, it is speculated that there is a "compromised regulation" mechanism in the body under the condition of neurological abnormalities.

Intradiscal injection of human recombinant BMP-4 does not reverse intervertebral disc degeneration induced by nuclectomy in sheep.

Background: Intervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-ß in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration. Methods: The effects of BMP-4 on ECM deposition and cell proliferation were assessed in sheep NP and annulus fibrosus (AF) cells in a pellet culture model. Further, a nuclectomy induced sheep lumbar IVD degeneration model was used to evaluate the safety and effects of intradiscal BMP-4 injection on IVD regeneration. Outcomes were assessed by magnetic resonance imaging, micro-computed tomography, histological and biochemical measurements. Results: In vitro, BMP-4 significantly increased the production of proteoglycan and deposition of collagen type II and proliferation of NP and AF cells. Collagen type I deposition was not affected in NP cells, while in AF cells it was high at low BMP-4 concentrations, and decreased with increasing concentration of BMP-4. Intradiscal injection of BMP-4 induced extradiscal new bone formation and Schmorl's node-like changes in vivo. No regeneration in the NP nor AF was observed. Conclusion: Our study demonstrated that although BMP-4 showed promising regenerative effects in vitro, similar effects were not observed in a large IVD degeneration animal model. The Translational Potential of This Article: The contradictory results of using BMP-4 on IVD regeneration between in vitro and in vivo demonstrate that direct BMP-4 injection for disc degeneration-associated human chronic low back pain should not be undertaken. In addition, our results may also shed light on the mechanisms behind pathological endplate changes in human patients as a possible target for therapy.

Radiographic evaluation of lumbar intervertebral disc height index: An intra and inter-rater agreement and reliability study.

PURPOSE: To evaluate intra- and inter-rater agreement and reliability of seven reported disc height index (DHI) measurement methods on standing lateral X-ray of lumbar spine. METHODS: The adult patients who had standing lateral X-ray of lumbar spine were recruited. Seven methods were used to measure DHI of each lumbar intervertebral disc level, including a ratio of sum of anterior and posterior disc height (DH) to disc diameter (Method 1), a ratio of middle DH to mid-vertebral body height (Method 2), a ratio of middle DH to disc diameter (Method 3), a ratio of the mean of anterior, middle, and posterior DH to the sagittal diameter of the proximal vertebral body (Method 4), a ratio of DH to vertebral height which cross the centre of adjacent vertebral bodies (Method 5), a ratio of the mean of anterior, middle, and posterior DH to the mean of proximal and distal vertebral body height (Method 6), and a ratio of the sum of anterior and posterior DH to the sum of superior and inferior disc depth (Method 7). Two raters conducted the measurements (one medical student (SS) and the other an experienced spine surgeon (XC)). Bland and Altmans Limits of Agreement (LOA) with standard difference were calculated to examine intra- and inter-rater agreements between two out of seven methods for DHI. Intra-class correlations (ICC) with 95% confidence intervals were calculated to assess intra- and inter-rater reliability. RESULTS: The intra-rater reliability in DHI measurements for 288 participants were ICCs from 0.807 (0.794, 0.812) to 0.922 (0.913, 0.946) by rater 1 (SS) and from 0.827 (0.802, 0.841) to 0.918 (0.806, 0.823) by rater 2 (XC). Method 2, 3, and 5 on all segmental levels had bias (95 % CI does not include zero) or/and out of the acceptable cut-off proportion (>50 %). A total of 609 outliers in 9174 segmental levels' LOA range. Inter-rater reliability was good-to-excellent in all but method 2 (0.736 (0.712, 0.759)) and method 5 (0.634 (0.598, 0.667)). ICCs of related lines to good-to-excellent reliability methods was excellent in all but only indirect lines in method 1 and 4 (ICCs lie in the range from 0.8 to 0.9). CONCLUSION: Following a structured protocol, intra- and inter-rater reliability was good-to-excellent for most DHI measurement methods on X-ray. However, the complicated methods (more indirect lines) and IVD degeneration (nucleus pulposus degeneration and disc herniation) potentially affected the agreement on inter-rater measurements. Method 7 is the best reproducible method to measure disc height index for all intervertebral disc segmental levels with a good-to-excellent intra- and inter-rater reliability and agreement.

Bone Marrow-Derived Mesenchymal Stem Cells Augment Regeneration of Intervertebral Disc in a Reproducible and Validated Mouse Intervertebral Disc Degeneration Model.

BACKGROUND: Back pain and radicular pain due to disc degeneration are probably the most common problems encountered in neurosurgical practice. The experience and results of stem cell therapy in animal disc degeneration model will help us while doing clinical trials. OBJECTIVE: To study the effect of bone marrow-derived mesenchymal stem cells in an established mouse disc degeneration model. METHODS: An easily reproducible mouse coccygeal (Co) 4-5 disc degenerated model by CT-guided percutaneous needle injury was established. The mesenchymal stem cells (MSCs) were cultured from mouse bone marrow and validated. By an established technique, 24 mice disc degenerative models were generated and divided equally into 3 groups (test, placebo, and control). The test group received MSCs with fibrin glue scaffold and placebo group received only scaffold after 6 weeks of degeneration. The control group did not receive any injection. The effects of MSCs were analyzed 8 weeks post injection. RESULTS: The test group showed a significant change in disc height index (%) in micro CT, whereas in the placebo and control groups, there was no change. The Safranin O staining showed an increase in glycosaminoglycan content and the polarized imaging of picrosirius red staining showed restoration of the collagen fibers in annulus fibrosus, which was statistically significant. CONCLUSION: Intradiscal MSC injection restored disc height and promoted regeneration in the discs at the end of 8 weeks. MSC's niche depends on the microenvironment of the host tissue. These findings will be helpful for clinical trials.

Development of a Unique Mouse Intervertebral Disc Degeneration Model Using a Simple Novel Tool.

STUDY DESIGN: Animal case control study. PURPOSE: To create a simple, reproducible disc degeneration model for mouse coccygeal vertebrae. OVERVIEW OF LITERATURE: Back pain due to disc degeneration is probably the most common problem encountered in neurosurgical practice. An easily reproducible animal model for disc degeneration will help in understanding its pathophysiology, and serve as a platform for examining various therapeutic options. METHODS: A total of 18 mice were divided into injured (n=12) and non-injured (n=6) groups. The disc height index (DHI%) at coccygeal 4-5 level was measured by computed tomography (CT) scan for all mice. Coccygeal 4-5 discs of the injury group were injured using a 32G needle fixed to a novel tool and confirmed by CT. The non-injury group underwent no procedure. DHI% was measured by CT at 2-, 4-, and 6-week post-injury, and all mice tails were sectioned for histopathology grading of disc degeneration at the respective time intervals. RESULTS: The injured group showed significant variation in DHI% at 2, 4, and 6 weeks, whereas there was no change in the noninjured group. Histopathologic evaluation with Safranin O stain showed a worsening of the disc degeneration score at 2, 4, and 6 weeks in the injured group, but in the non-injured group there was no change. Percutaneous needle injury technique with our novel tool provided 100% accuracy and uniform degeneration. CONCLUSIONS: A simple, easily reproducible mouse model for disc degeneration was created using a simple, cost-effective, novel tool and technique, its advantage being high precision and user friendly.

Endoscopic posterior decompression under local anesthesia for degenerative lumbar spinal stenosis.

OBJECTIVEVarious minimally invasive techniques have been described for the decompression of lumbar spinal stenosis (LSS). However, few reports have described the results of endoscopic posterior decompression (EPD) with laminectomy performed under local anesthesia. This study aimed to evaluate the clinical and radiological outcomes of EPD performed under local anesthesia in patients with LSS and to compare the procedural outcomes in patients with and without preoperative spondylolisthesis.METHODSFifty patients (28 female and 22 male) who underwent EPD under local anesthesia were included in this study. Patients were assessed before surgery and were followed up with regular outpatient visits (at 1, 3, 6, 12, and 24 months postoperatively). Clinical outcomes were evaluated using the visual analog scale (VAS), Oswestry Disability Index (ODI), and the 36-Item Short Form Survey (SF-36) outcome questionnaire. Radiological outcomes were assessed by measuring lumbar lordosis, disc-wedging angle, percentage of vertebral slippage, and disc height index on plain standing radiographs.RESULTSThe VAS, ODI, and SF-36 scores were significantly improved at 1 month after surgery compared to the baseline mean values, and the improved scores were maintained over the 2-year follow-up period. Radiological progression was found in 2 patients during the follow-up period. Patients with and without preoperative spondylolisthesis had no significant differences in their clinical and radiological outcomes.CONCLUSIONSEPD performed under local anesthesia is effective for LSS treatment. Similar favorable outcomes can be obtained in patients with and without preoperative spondylolisthesis using this approach.

A percutaneous, minimally invasive annulus fibrosus needle puncture model of intervertebral disc degeneration in rabbits.

PURPOSE: Various animal models have been proposed to mimic the pathophysiologic process of intervertebral disc degeneration, a leading cause of back pain. The purpose of this study is to describe a minimally invasive technique via percutaneous needle puncture of the annulus fibrosus in New Zealand white rabbits. METHODS: Under fluoroscopic guidance, an 18-gauge spinal needle was inserted 2 cm lateral to the midline spinous process. The needle was slowly advanced at approximately 45° angle until it was adjacent to the L5/L6 disc space. Lateral and anteroposterior views were used to verify correct needle position before advancing into the nucleus pulposus. The rabbits underwent weekly X-rays for 4 weeks to assess disc height index. MRI T2 relaxation was evaluated at week four to assess morphological changes. Discs were histologically graded on a 12-point scale to assess degeneration and compared to discs obtained from uninjured rabbits. RESULTS: There were no complications associated with the percutaneous needle puncture procedure. All animals survived the duration of the experiment. Four weeks after injury, the disc height had progressively narrowed to approximately 50% of baseline. MRI assessment at the 4-week time point demonstrated a mean T2 relaxation time at the L5/L6 level that was 20.9% of the T2 relaxation time at the uninjured L4/L5 disc level ( p < 0.001). Histological analysis demonstrated lamellar disorganization of the annulus and decreased cellularity and proteoglycan content within the injured nucleus compared to uninjured control discs. CONCLUSION: The present study demonstrated a reliable technique of inducing an annular tear via a percutaneous needle puncture. Compared to open surgical approaches, the percutaneous model produces similar progressive disc degeneration while minimizing harm to the animal subjects. CLINICAL RELEVANCE: The present study establishes a technique for the introduction of novel therapeutic agents to treat disc degeneration that may translate to future clinical trials.

Quantitative MRI correlates with histological grade in a percutaneous needle injury mouse model of disc degeneration.

Low back pain due to disc degeneration is a major cause of morbidity and health care expenditures worldwide. While stem cell-based therapies hold promise for disc regeneration, there is an urgent need to develop improved in vivo animal models to further develop and validate these potential treatments. The objectives of this study were to characterize a percutaneous needle injury model of intervertebral disc degeneration in the mouse caudal spine, and compare two non-invasive quantitative imaging techniques, microcomputed tomography and magnetic resonance imaging (MRI), as effective measures of disc degeneration in this model. Percutaneous needle injury of mouse caudal discs was undertaken using different needle sizes and injury types (unilateral or bilateral annulus fibrosus (AF) puncture). Mice were euthanized 4 weeks post-injury, and MRI and microcomputed tomography were used to determine T2 relaxation time of the NP and disc height index, respectively. Disc condition was then further assessed using semi-quantitative histological grading. Bilateral AF puncture with either 27 or 29G needles resulted in significantly lower T2 relaxation times compared to uninjured controls, while disc height index was not significantly affected by any injury type. There was a strong, inverse linear relationship between histological grade and NP T2 relaxation time. In this study, we demonstrated that quantitative MRI can detect disc degeneration in the mouse caudal spine 4 weeks following percutaneous needle injury, and may therefore serve as a surrogate for histology in longitudinal studies of both disc degeneration and cell-based therapies for disc regeneration using this model. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2771-2779, 2018.

Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.

OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.

Outcomes in cases of lumbar degenerative spondylolisthesis more than 5 years after treatment with minimally invasive decompression: examination of pre- and postoperative slippage, intervertebral disc changes, and clinical results.

OBJECT: There are reports that fusion is the standard treatment of choice for cases of lumbar degenerative spondylolisthesis (LDS) associated with lumbar spinal canal stenosis with a large degree of slippage. The reasons why, however, have not been clarified. On the other hand, it is known that the progress of slippage decreases and restabilization occurs over the natural course of LDS. Therefore, if minimally invasive decompression could be performed, there would be little possibility of it influencing the natural course of LDS, so it would not be necessary to include preoperative percentage slip in the criteria for the selection of fusion. This study examined the course of LDS cases more than 5 years after treatment with minimally invasive decompression to determine whether pre- and postoperative slippage and disc changes influence the clinical results. METHODS: A total of 51 intervertebral segments in 51 cases with the chief complaint of radicular or cauda equina symptoms due to lumbar spinal canal stenosis were examined after prospective treatment with minimally invasive decompression for LDS. The mean age of the patients at the time of surgery was 66.7 years and the mean follow-up period was 7 years 4 months. Minimally invasive decompression was performed regardless of the degree of low-back pain or percentage slip. The outcome variables were clinical results and changes in imaging findings. RESULTS: Over the follow-up period, postoperative percentage slip increased and disc height decreased, but the Japanese Orthopaedic Association score improved. Regardless of the preoperative percentage slip, disc height, or degree of intervertebral disc degeneration or segmental instability, the clinical results were favorable. In the high preoperative percentage slip group, low disc height group, and progressive disc degeneration group, there was little postoperative progress of slippage. In the group with a postoperative slippage increase of more than 5%, slippage increased significantly at postoperative year 2, but no significant difference was observed at the final follow-up. CONCLUSIONS: When minimally invasive decompression was performed to treat LDS, the postoperative change in slippage was no different from that during the natural course. Furthermore, regardless of the degree of preoperative slippage or intervertebral disc degeneration, the clinical results were favorable. Also, the higher the preoperative percentage slip and the more that disc degeneration progressed, the more the progress of postoperative slippage decreased. Because the postoperative progress of slippage decreased, it is believed that even after minimally invasive decompression, restabilization occurs as it would during the natural course. If minimally invasive decompression can be performed to treat LDS, it is believed that preoperative percentage slip and intervertebral disc degeneration do not have to be included in the appropriateness criteria for fusion.

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model.

OBJECT: Following microdiscectomy, discs generally fail to undergo spontaneous regeneration and patients may experience chronic low-back pain and recurrent disc prolapse. In published studies, formulations of mesenchymal progenitor cells combined with pentosan polysulfate (MPCs+PPS) have been shown to regenerate disc tissue in animal models, suggesting that this approach may provide a useful adjunct to microdiscectomy. The goal of this preclinical laboratory study was to determine if the transplantation of MPCs+PPS, embedded in a gelatin/fibrin scaffold (SCAF), and transplanted into a defect created by microdiscectomy, could promote disc regeneration. METHODS: A standardized microdiscectomy procedure was performed in 18 ovine lumbar discs. The subsequent disc defects were randomized to receive either no treatment (NIL), SCAF only, or the MPC+PPS formulation added to SCAF (MPCs+PPS+SCAF). Necropsies were undertaken 6 months postoperatively and the spines analyzed radiologically (radiography and MRI), biochemically, and histologically. RESULTS: No adverse events occurred throughout the duration of the study. The MPC+PPS+SCAF group had significantly less reduction in disc height compared with SCAF-only and NIL groups (p < 0.05 and p < 0.01, respectively). Magnetic resonance imaging Pfirrmann scores in the MPC+PPS+SCAF group were significantly lower than those in the SCAF group (p = 0.0213). The chaotropic solvent extractability of proteoglycans from the nucleus pulposus of MPC+PPS+SCAF-treated discs was significantly higher than that from the SCAF-only discs (p = 0.0312), and using gel exclusion chromatography, extracts from MPC+PPS+SCAF-treated discs also contained a higher percentage of proteoglycan aggregates than the extracts from both other groups. Analysis of the histological sections showed that 66% (p > 0.05) of the MPC+PPS+SCAF-treated discs exhibited less degeneration than the NIL or SCAF discs. CONCLUSIONS: These findings demonstrate the capacity of MPCs in combination with PPS, when embedded in a gelatin sponge and sealed with fibrin glue in a microdiscectomy defect, to restore disc height, disc morphology, and nucleus pulposus proteoglycan content.