SOD2 orchestrates redox homeostasis in intervertebral discs: A novel insight into oxidative stress-mediated degeneration and therapeutic potential.

Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebral disc (IVD) degeneration. Although oxidative stress has been shown to contribute to IVD degeneration, the underlying mechanisms remain undetermined. This study aimed to unravel the role of superoxide dismutase 2 (SOD2) in IVD pathogenesis and target oxidative stress to limit IVD degeneration. SOD2 demonstrated a dynamic regulation in surgically excised human IVD tissues, with initial upregulation in moderate degeneration and downregulation in severely degenerated IVDs. Through a comprehensive set of in vitro and in vivo experiments, we found a suggestive association between excessive mitochondrial superoxide, cellular senescence, and matrix degradation in human and mouse IVD cells. We confirmed that aging and mechanical stress, established triggers for IVD degeneration, escalated mitochondrial superoxide levels in mouse models. Critically, chondrocyte-specific Sod2 deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, and could be attenuated by ß-nicotinamide mononucleotide treatment. These revelations underscore the central role of SOD2 in IVD redox balance and unveil potential therapeutic avenues, making SOD2 and mitochondrial superoxide promising targets for effective LBP interventions.

ISSLS PRIZE in Basic Science 2024: superiority of nucleus pulposus cell- versus mesenchymal stromal cell-derived extracellular vesicles in attenuating disc degeneration and alleviating pain.

PURPOSE: To investigate the therapeutic potential of extracellular vesicles (EVs) derived from human nucleus pulposus cells (NPCs), with a specific emphasis on Tie2-enhanced NPCs, compared to EVs derived from human bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a coccygeal intervertebral disc degeneration (IDD) rat model. METHODS: EVs were isolated from healthy human NPCs cultured under standard (NPCSTD-EVs) and Tie2-enhancing (NPCTie2+-EVs) conditions. EVs were characterized, and their potential was assessed in vitro on degenerative NPCs in terms of cell proliferation and senescence, with or without 10 ng/mL interleukin (IL)-1ß. Thereafter, 16 Sprague-Dawley rats underwent annular puncture of three contiguous coccygeal discs to develop IDD. Phosphate-buffered saline, NPCSTD-EVs, NPCTie2+-EVs, or BM-MSC-derived EVs were injected into injured discs, and animals were followed for 12 weeks until sacrifice. Behavioral tests, radiographic disc height index (DHI) measurements, evaluation of pain biomarkers, and histological analyses were performed to assess the outcomes of injected EVs. RESULTS: NPC-derived EVs exhibited the typical exosomal morphology and were efficiently internalized by degenerative NPCs, enhancing cell proliferation, and reducing senescence. In vivo, a single injection of NPC-derived EVs preserved DHI, attenuated degenerative changes, and notably reduced mechanical hypersensitivity. MSC-derived EVs showed marginal improvements over sham controls across all measured outcomes. CONCLUSION: Our results underscore the regenerative potential of young NPC-derived EVs, particularly NPCTie2+-EVs, surpassing MSC-derived counterparts. These findings raise questions about the validity of MSCs as both EV sources and cellular therapeutics against IDD. The study emphasizes the critical influence of cell type, source, and culture conditions in EV-based therapeutics.

Threats and opportunities of using ChatGPT in scientific writing-The risk of getting spineless.

ChatGPT and AI chatbots are revolutionizing several science fields, including medical writing. However, the inadequate use of such advantageous tools can raise numerous methodological and ethical issues.

Recombinant Laminin-511 Fragment (iMatrix-511) Coating Supports Maintenance of Human Nucleus Pulposus Progenitor Cells In Vitro.

The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the challenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2+ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative potential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG)) and their ability to form spherical colonies within methylcellulose hydrogels. Lami-coat significantly enhanced cell proliferation rates and increased Tie2 expression, resulting in a 7.9-fold increase in Tie2-expressing cell yields. Moreover, the overall proportion of cells positive for Tie2 also increased 2.7-fold. Notably, the Col2 positivity rate was significantly higher on laminin-coated plates (Non-coat: 10.24% (±1.7%) versus Lami-coat: 26.2% (±7.5%), p = 0.010), and the ability to form spherical colonies also showed a significant improvement (Non-coat: 40.7 (±8.8)/1000 cells versus Lami-coat: 70.53 (±18.0)/1000 cells, p = 0.016). These findings demonstrate that Lami-coat enhances the potential of NP cells, as indicated by improved colony formation and proliferative characteristics. This highlights the potential of laminin-coating in maintaining the NP progenitor cell phenotype in culture, thereby supporting their translation into prospective clinical cell-transplantation products.

Investigation of the Mitigation of DMSO-Induced Cytotoxicity by Hyaluronic Acid following Cryopreservation of Human Nucleus Pulposus Cells.

To develop an off-the-shelf therapeutic product for intervertebral disc (IVD) repair using nucleus pulposus cells (NPCs), it is beneficial to mitigate dimethyl sulfoxide (DMSO)-induced cytotoxicity caused by intracellular reactive oxygen species (ROS). Hyaluronic acid (HA) has been shown to protect chondrocytes against ROS. Therefore, we examined the potential of HA on mitigating DMSO-induced cytotoxicity for the enhancement of NPC therapy. Human NPC cryopreserved in DMSO solutions were thawed, mixed with equal amounts of EDTA-PBS (Group E) or HA (Group H), and incubated for 3-5 h. After incubation, DMSO was removed, and the cells were cultured for 5 days. Thereafter, we examined cell viability, cell proliferation rates, Tie2 positivity (a marker of NP progenitor cells), and the estimated numbers of Tie2 positive cells. Fluorescence intensity of DHE and MitoSOX staining, as indicators for oxidative stress, were evaluated by flow cytometry. Group H showed higher rates of cell proliferation and Tie2 expressing cells with a trend toward suppression of oxidative stress compared to Group E. Thus, HA treatment appears to suppress ROS induced by DMSO. These results highlight the ability of HA to maintain NPC functionalities, suggesting that mixing HA at the time of transplantation may be useful in the development of off-the-shelf NPC products.

Adolescent Idiopathic Scoliotic Deformity Correction Surgery Assisted by Smart Glasses Can Enhance Correction Outcomes and Accuracy and Also Improve Surgeon Fatigue.

OBJECTIVE: Augmented reality (AR) is becoming more common and slowly being integrated into the surgical field. With the continuous progression of navigation and visualization techniques, AR has great potential to improve surgical quality and safety. Nevertheless, the effects of AR on surgical outcomes and surgeons' well-being remains poorly studied. The present prospective controlled study aims to assess the effect of surgery assisted with AR smart glasses on adolescent idiopathic scoliosis (AIS) deformity correction outcomes and surgeon fatigue. METHODS: AIS patients scheduled for surgical deformity correction were prospectively recruited and assigned to standard or AR-supported surgery, using lightweight AR smart glasses. The demographic and clinical features were recorded. The pre- and postoperative spinal features, operative time, and blood loss were recorded and compared. Finally, the participating surgeons were asked to complete a questionnaire (e.g., visual analog scale for fatigue) to compare the effects of AR on their well-being. RESULTS: Our results have shown enhanced spinal deformity corrections with Cobb angle (-35.7° vs. -46.9°), thoracic kyphosis (8.1° vs. 11.6°), and vertebral rotation (-9.3° vs. -13.8°) changes favoring AR-supported surgery. Moreover, AR resulted in significantly lower violation rates per patient (7.5% vs. 6.6%; P = 0.023). Finally, the visual analog scale for fatigue scores consistently showed a significant reduction in fatigue (5.7 ± 1.7 vs. 3.3 ± 1.2; P < 0.001) and other fatigue classifiers for the surgeons after AR-supported surgery. CONCLUSIONS: Our controlled study has highlighted the enhanced spinal correction rates in AR-supported surgery and also improved surgeons' well-being and fatigue. These results endorse the adaptation of AR techniques to support AIS surgical correction.

Harmonization and standardization of nucleus pulposus cell extraction and culture methods.

Background: In vitro studies using nucleus pulposus (NP) cells are commonly used to investigate disc cell biology and pathogenesis, or to aid in the development of new therapies. However, lab-to-lab variability jeopardizes the much-needed progress in the field. Here, an international group of spine scientists collaborated to standardize extraction and expansion techniques for NP cells to reduce variability, improve comparability between labs and improve utilization of funding and resources. Methods: The most commonly applied methods for NP cell extraction, expansion, and re-differentiation were identified using a questionnaire to research groups worldwide. NP cell extraction methods from rat, rabbit, pig, dog, cow, and human NP tissue were experimentally assessed. Expansion and re-differentiation media and techniques were also investigated. Results: Recommended protocols are provided for extraction, expansion, and re-differentiation of NP cells from common species utilized for NP cell culture. Conclusions: This international, multilab and multispecies study identified cell extraction methods for greater cell yield and fewer gene expression changes by applying species-specific pronase usage, 60-100 U/ml collagenase for shorter durations. Recommendations for NP cell expansion, passage number, and many factors driving successful cell culture in different species are also addressed to support harmonization, rigor, and cross-lab comparisons on NP cells worldwide.

Homing of vertebral-delivered mesenchymal stromal cells for degenerative intervertebral discs repair - an in vivo proof-of-concept study.

Introduction: Cell transplantation shows promising results for intervertebral disc (IVD) repair, however, contemporary strategies present concerns regarding needle puncture damage, cell retention, and straining the limited nutrient availability. Mesenchymal stromal cell (MSC) homing is a natural mechanism of long-distance cellular migration to sites of damage and regeneration. Previous ex vivo studies have confirmed the potential of MSC to migrate over the endplate and enhance IVD-matrix production. In this study, we aimed to exploit this mechanism to engender IVD repair in a rat disc degeneration model. Methods: Female Sprague Dawley rats were subjected to coccygeal disc degeneration through nucleus pulposus (NP) aspiration. In part 1; MSC or saline was transplanted into the vertebrae neighboring healthy or degenerative IVD subjected to irradiation or left untouched, and the ability to maintain the IVD integrity for 2 and 4 weeks was assessed by disc height index (DHI) and histology. For part 2, ubiquitously GFP expressing MSC were transplanted either intradiscally or vertebrally, and regenerative outcomes were compared at days 1, 5, and 14 post-transplantation. Moreover, the homing potential from vertebrae to IVD of the GFP+ MSC was assessed through cryosection mediated immunohistochemistry. Results: Part 1 of the study revealed significantly improved maintenance of DHI for IVD vertebrally receiving MSC. Moreover, histological observations revealed a trend of IVD integrity maintenance. Part 2 of the study highlighted the enhanced DHI and matrix integrity for discs receiving MSC vertebrally compared with intradiscal injection. Moreover, GFP rates highlighted MSC migration and integration in the IVD at similar rates as the intradiscally treated cohort. Conclusion: Vertebrally transplanted MSC had a beneficial effect on the degenerative cascade in their neighboring IVD, and thus potentially present an alternative administration strategy. Further investigation will be needed to determine the long-term effects, elucidate the role of cellular homing versus paracrine signaling, and validate our observations on a large animal model.

Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain.

Background: Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain (LBP) and despite a prominent prevalence, present treatment options remain inadequate for a large portion of LBP patients. New developments in regenerative therapeutics offer potentially powerful medical tools to modify this pathology, with specific focus on (stem) cell transplantations. Multiple clinical trials have since reported overall beneficial outcomes favoring cell therapy. Nonetheless, the significance of these improvements is often not (clearly) discussed. As such, this narrative review aims to summarize the significance of the reported improvements from human clinical trials on IVD-targeted cell therapy. Methods: Through a comprehensive narrative review we discuss the improvements in pain, disability, quality of life, and imaging modalities and reported adverse events following cell therapy for discogenic pain. Results: Most clinical trials were able to report clear and significant improvements in pain and disability outcomes. Imaging and quality of life improvements however were not as clearly reported but did present some enhancements for a select number of patients. Finally, whether cell therapy can outperform placebo treatment remains intangible. Conclusions: Our review highlights the clinical significance of observed trends in pain and disability improvement. Nevertheless, reporting quality was found unsatisfactory and large-scale randomized controlled studies remain small in number. Future studies and articles should put more emphasis on improvements in imaging modalities and compare outcomes to (placebo) control groups to fully elucidate the efficacy and safety of cellular therapeutics against LBP.

Low Radiation Protocol for Intraoperative Robotic C-Arm Can Enhance Adolescent Idiopathic Scoliosis Deformity Correction Accuracy and Safety.

STUDY DESIGN: Retrospective case-series study. OBJECTIVES: To assess (1) low cone beam CT (CBCT) mediated intraoperative navigation to limit radiation exposure without compromising surgical accuracy, and (2) the potential of intraoperative C-arm CBCT navigation to augment pedicle screw (PS) placement accuracy in AIS surgery compared to pre-surgery CT-based planning. METHODS: The first part involved a prospective phantom study, comparing radiation doses for conventional CT, and standard (6sDCT) and a low dose (5sDCT) Artis Zeego®-imaging. Next, 5sDCT- and 6sDCT-navigation were compared on PS accuracy and radiation exposure during AIS correction. The final part compared surgical AIS deformity correction through intraoperative 5sDCT navigation to a matched cohort treated using conventional pre-surgery CT-scans for navigation. Outcome parameters included operation time, skin dose (SD), dose area product (DAP), intraoperative blood loss, postoperative complications, and PS deviation rates. RESULTS: The phantom study demonstrated a reduction in radiation for the 5sDCT protocol. Moreover, 5sDCT-imaged patients (n = 15) showed a significantly lower SD (-27.41%) and DAP (-30.92%), without compromising PS accuracy compared with 6sDCT-settings (n = 15). Finally, AIS correction through intraoperative CBCT C-arm navigation (n = 27) significantly reduced screw deviation rates (6.83% versus 10.75%, P = .016) without increasing operation times, compared with conventional CT (n = 37). CONCLUSIONS: Intraoperative navigation using a CBCT C-arm system improved the accuracy of PS insertion and reduced surgery time. Moreover, it reduced radiation exposure compared with conventional CT, which was further curtailed by adapting the low-dose 5sDCT protocol. In short, our study highlights the benefits of intraoperative CBCT navigation for PS placement in AIS surgery.

Multicenter Retrospective Analysis of Intradiscal Condoliase Injection Therapy for Lumbar Disc Herniation.

Background and Objectives: Intradiscal injection of Condoliase (chondroitin sulfate ABC endolyase), a glycosaminoglycan-degrading enzyme, is employed as a minimally invasive treatment for lumbar disc herniation (LDH) and represents a promising option between conservative treatment and surgical intervention. Since its 2018 approval in Japan, multiple single-site trails have highlighted its effectiveness, however, the effect of LDH types, and influences of patient age, sex, etc., on treatment success remains unclear. Moreover, data on teenagers and elderly patients has not been reported. In this retrospective multi-center study, we sought to classify prognostic factors for successful condoliase treatment for LDH and assess its effect on patients < 20 and ≥70 years old. Materials and Methods: We reviewed the records of 137 LDH patients treated through condoliase at four Japanese institutions and assessed its effectiveness among different age categories on alleviation of visual analog scale (VAS) of leg pain, low back pain and numbness, as well as ODI and JOA scores. Moreover, we divided them into either a "group-A" category if a ≥50% improvement in baseline leg pain VAS was observed or "group-N" if VAS leg pain improved <50%. Next, we assessed the differences in clinical and demographic distribution between group-A and group-N. Results: Fifty-five patients were classified as group-A (77.5%) and 16 patients were allocated to group-N (22.5%). A significant difference in Pfirrmann classification was found between both cohorts, with grade IV suggested to be most receptive. A posterior disc angle > 5° was also found to approach statical significance. In all age groups, average VAS scores showed improvement. However, 75% of adolescent patients showed deterioration in Pfirrmann classification following treatment. Conclusions: Intradiscal condoliase injection is an effective treatment for LDH, even in patients with large vertebral translation and posterior disc angles, regardless of age. However, since condoliase imposes a risk of progressing disc degeneration, its indication for younger patients remains controversial.

Clinical Development of Regenerative Medicine Targeted for Intervertebral Disc Disease.

Low back pain is critical health, social, and economic issue in modern societies. This disease is often associated with intervertebral disc degeneration; however, contemporary treatments are unable to target this underlying pathology to alleviate the pain symptoms. Cell therapy offers a promising novel therapeutic that, in theory, should be able to reduce low back pain through mitigating the degenerative disc environment. With the clinical development of cell therapeutics ongoing, this review aims to summarize reporting on the different clinical trials and assess the different regenerative strategies being undertaken to collectively obtain an impression on the potential safety and effectiveness of cell therapeutics against intervertebral disc-related diseases.

Predictive Factors for Successful Treatment of Deep Incisional Surgical Site Infections following Instrumented Spinal Surgeries: Retrospective Review of 1832 Cases.

BACKGROUND: Surgical site infection (SSI) is a major complication in spinal instrumentation that is often difficult to treat. The purpose of this study was to identify and determine prognostic indicators for successful treatment of spine instrumentation SSI. METHODS: Retrospectively, spine surgery cases were examined on SSI diagnosis. Post-instrumentation SSI patients were categorized as "Successful" if SSI subsided after single debridement. Patients in whom SSI did not subsided and/or required removal of instrumentation were classified as "Challenging". We investigated the relation of treatment outcomes to patients and treatment factors. RESULTS: A total of 1832 spinal instrumentation cases were recognized with 44 (2.40%) SSI cases. White blood cell count, C-reactive protein (CRP) levels, causative bacteria (i.e., S. Aureus or MRSA), trauma injury, and early-stage antimicrobial agent sensitivity correlated with treatment prognosis. Multivariate analysis highlighted CRP levels and applying early-stage sensitive antibiotics as potential impactful predictive factors for successful treatment. CONCLUSIONS: Our results demonstrated that early selection of sensitive antimicrobial agents is critical and emphasizes the potential for early-stage classification methods such as Gram staining. Additionally, S. Aureus and MRSA SSI formed significantly more challenging infections to treat, thus requiring consideration when deciding on instrumentation retention. These factors offer promising aspects for further large-scale studies.

N-acetylcysteine attenuates oxidative stress-mediated cell viability loss induced by dimethyl sulfoxide in cryopreservation of human nucleus pulposus cells: A potential solution for mass production.

Background: Cell therapy is considered a promising strategy for intervertebral disc (IVD) regeneration. However, cell products often require long-term cryopreservation, which compromises cell viability and potency, thus potentially hindering commercialization and off-the-shelf availability. Dimethyl sulfoxide (DMSO) is a commonly used cryoprotectant, however, DMSO is associated with cytotoxicity and cell viability loss. This study aimed to investigate the effects of DMSO on human nucleus pulposus cells (NPC) and the role of oxidative stress in DMSO-induced cytotoxicity. Furthermore, we examined the potential of antioxidant N-acetylcysteine (NAC) supplementation to mitigate the negative effects of DMSO. Methods: NPC were exposed to various concentrations of DMSO with or without a freezing cycle. Cell viability, cell apoptosis and necrosis rates, intracellular reactive oxygen species (ROS) levels, and gene expression of major antioxidant enzymes were evaluated. In addition, NAC was added to cryopreservation medium containing 10% DMSO and its effects on ROS levels and cell viability were assessed. Results: DMSO concentrations ≤1% for 24 h did not significantly affect the NPC viability, whereas exposure to 5 and 10% DMSO (most commonly used concentration) caused cell viability loss (loss of 57% and 68% respectively after 24 h) and cell death in a dose- and time-dependent manner. DMSO increased intracellular and mitochondrial ROS (1.9-fold and 3.6-fold respectively after 12 h exposure to 10% DMSO) and downregulated gene expression levels of antioxidant enzymes in a dose-dependent manner. Tempering ROS through NAC treatment significantly attenuated DMSO-induced oxidative stress and supported maintenance of cell viability. Conclusions: This study demonstrated dose- and time-dependent cytotoxic effects of DMSO on human NPC. The addition of NAC to the cryopreservation medium ameliorated cell viability loss by reducing DMSO-induced oxidative stress in the freeze-thawing cycle. These findings may be useful for future clinical applications of whole cells and cellular products.

Development of a standardized histopathology scoring system for intervertebral disc degeneration and regeneration in rabbit models-An initiative of the ORSspine section.

BACKGROUND: The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre-clinical evaluation of regenerative therapies. Histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models. AIMS: The purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model. MATERIALS AND METHODS: The scoring system was formulated following a review of the literature and a survey of spine researchers. Validation of the scoring system was carried out using images provided by 4 independent laboratories, which were graded by 12 independent graders of varying experience levels. Reliability testing was performed via the computation of intra-class correlation coefficients (ICC) for each category and the total score. The scoring system was then further refined based on the results of the ICC analysis and discussions amongst the authors. RESULTS: The final general scoring system involves scoring 7 features (nucleus pulposus shape, area, cellularity and matrix condensation, annulus fibrosus/nucleus pulposus border appearance, annulus fibrosus morphology, and endplate sclerosis/thickening) on a 0 (healthy) to 2 (severe degeneration) scale. ICCs demonstrated overall moderate to good agreement across graders. An addendum to the main scoring system is also included for use in studies evaluating regenerative therapeutics, which involves scoring cell cloning and morphology within the nucleus pulposus and inner annulus fibrosus. DISCUSSION: Overall, this new scoring system provides an avenue to improve standardization, allow a more accurate comparison between labs and more robust evaluation of pathophysiology and regenerative treatments across the field. CONCLUSION: This study developed a histopathology scoring system for degeneration and regeneration in the rabbit model based on reported practice in the literature, a survey of spine researchers, and validation testing.

Development of a standardized histopathology scoring system for intervertebral disc degeneration in rat models: An initiative of the ORS spine section.

BACKGROUND: Rats are a widely accepted preclinical model for evaluating intervertebral disc (IVD) degeneration and regeneration. IVD morphology is commonly assessed using histology, which forms the foundation for quantifying the state of IVD degeneration. IVD degeneration severity is evaluated using different grading systems that focus on distinct degenerative features. A standard grading system would facilitate more accurate comparison across laboratories and more robust comparisons of different models and interventions. AIMS: This study aimed to develop a histology grading system to quantify IVD degeneration for different rat models. MATERIALS & METHODS: This study involved a literature review, a survey of experts in the field, and a validation study using 25 slides that were scored by 15 graders from different international institutes to determine inter- and intra-rater reliability. RESULTS: A new IVD degeneration grading system was established and it consists of eight significant degenerative features, including nucleus pulposus (NP) shape, NP area, NP cell number, NP cell morphology, annulus fibrosus (AF) lamellar organization, AF tears/fissures/disruptions, NP-AF border appearance, as well as endplate disruptions/microfractures and osteophyte/ossification. The validation study indicated this system was easily adopted, and able to discern different severities of degenerative changes from different rat IVD degeneration models with high reproducibility for both experienced and inexperienced graders. In addition, a widely-accepted protocol for histological preparation of rat IVD samples based on the survey findings include paraffin embedding, sagittal orientation, section thickness < 10 µm, and staining using H&E and/or SO/FG to facilitate comparison across laboratories. CONCLUSION: The proposed histological preparation protocol and grading system provide a platform for more precise comparisons and more robust evaluation of rat IVD degeneration models and interventions across laboratories.

Effect of Whole Tissue Culture and Basic Fibroblast Growth Factor on Maintenance of Tie2 Molecule Expression in Human Nucleus Pulposus Cells.

Previous work showed a link between Tie2+ nucleus pulposus progenitor cells (NPPC) and disc degeneration. However, NPPC remain difficult to maintain in culture. Here, we report whole tissue culture (WTC) combined with fibroblast growth factor 2 (FGF2) and chimeric FGF (cFGF) supplementation to support and enhance NPPC and Tie2 expression. We also examined the role of PI3K/Akt and MEK/ERK pathways in FGF2 and cFGF-induced Tie2 expression. Young herniating nucleus pulposus tissue was used. We compared WTC and standard primary cell culture, with or without 10 ng/mL FGF2. PI3K/Akt and MEK/ERK signaling pathways were examined through western blotting. Using WTC and primary cell culture, Tie2 positivity rates were 7.0 ± 2.6% and 1.9 ± 0.3% (p = 0.004), respectively. Addition of FGF2 in WTC increased Tie2 positivity rates to 14.2 ± 5.4% (p = 0.01). FGF2-stimulated expression of Tie2 was reduced 3-fold with the addition of the MEK inhibitor PD98059 (p = 0.01). However, the addition of 1 µM Akt inhibitor, 124015-1MGCN, only reduced small Tie2 expression (p = 0.42). cFGF similarly increased the Tie2 expression, but did not result in significant phosphorylation in both the MEK/ERK and PI3K/Akt pathways. WTC with FGF2 addition significantly increased Tie2 maintenance of human NPPC. Moreover, FGF2 supports Tie2 expression via MEK/ERK and PI3K/Akt signals. These findings offer promising tools and insights for the development of NPPC-based therapeutics.

Cobalt-chromium versus titanium alloy rods for correction of adolescent idiopathic scoliosis based on 1-year follow-up: a multicenter randomized controlled clinical trial.

OBJECTIVE: For instrumented correction surgery for adolescent idiopathic scoliosis (AIS), surgeons are increasingly switching from titanium (Ti) alloy rods to stiffer cobalt-chromium (CoCr) rods. The authors conducted the first multicenter randomized controlled clinical trial to investigate whether these materials affect the outcomes in terms of spine correction and quality of life (QOL). This trial was registered at UMIN Clinical Trials Registry on September 3, 2012, under the identifier UMIN000008838 (level of evidence 1). METHODS: Female AIS patients (Lenke types 1-3, patient age 10-19 years) were recruited at 5 Japanese institutions and randomized into two cohorts: 6.0-mm-diameter Ti rods were placed in one group, and 6.0-mm-diameter CoCr rods were placed in the other. Patients were followed up at 2 weeks and 3, 6, and 12 months with radiographic examination to quantify the sagittal and coronal correction (Cobb angle, thoracic kyphosis, rib hump, and apical vertebral rotation). Patients completed questionnaires (Scoliosis Research Society-22r, 12-Item Short-Form Health Survey, and Scoliosis Japanese Questionnaire-27) at 6 and 12 months to assess QOL. RESULTS: A total of 69 AIS patients were randomized to the demographically similar Ti (n = 37) or CoCr (n = 32) cohort. Four adverse events were recorded, two in each cohort, but these were not related to the rod material. At the final follow-up, both Ti and CoCr cohorts showed significant improvement in spinal correction, including the Cobb angle, thoracic kyphosis, and rib hump size. The correction rates were 68.4% and 67.1% for the Ti and CoCr cohorts, respectively. No parameters differed significantly between the cohorts at any time. Survey data showed improved but similar outcomes in both cohorts. CONCLUSIONS: Both treatments (Ti and CoCr) produced similar results and were efficient in engendering clinically significant spine corrections. Clinical trial registration no.: UMIN000008838 (UMIN Clinical Trials Registry).

Simultaneous translation on two rods improves the correction and apex translocation in adolescent patients with hypokyphotic scoliosis.

OBJECTIVE: The objectives of this study were to apply the simultaneous translation on two rods (ST2R) maneuver involving rods contoured with a convexity at the desired thoracic kyphosis (TK) apex level and to assess the effects on the ability to support triplanar deformity corrections, including TK apex improvement, in patients with hypokyphotic adolescent idiopathic scoliosis (AIS). METHODS: Using retrospective analysis, the authors examined the digital records that included 2- to 4-week, 1-year, and 2-year postoperative radiographic follow-up data of female hypokyphotic (TK < 20°) AIS patients (Lenke type 1-3) treated with ST2R. The authors assessed the corrections of triplanar deformities by examining the main Cobb angle, TK, rib hump, apical vertebral rotation, Scoliosis Research Society 22-item questionnaire scores, and TK apex translocation. In order to better grasp the potential of ST2R, the outcomes were compared with those of a historical matched case-control cohort treated with a standard rod rotation (RR) maneuver. RESULTS: Data were analyzed for 25 AIS patients treated with ST2R and 27 patients treated with RR. The ST2R group had significant improvements in the main Cobb angle and TK, reduction in the rib hump size at each time point, and a final correction rate of 72%. ST2R treatment significantly increased the kyphosis apex by an average of 2.2 levels. The correction rate was higher at each time point in the ST2R group than in the RR group. ST2R engendered favorable TK corrections, although the differences were nonsignificant, at 2 years compared with the RR group (p = 0.056). The TK apex location was significantly improved in the ST2R cohort (p < 0.001). At the 1-month follow-up, hypokyphosis was resolved in 92% of the ST2R cohort compared with 30% of the RR cohort. CONCLUSIONS: Resolving hypokyphotic AIS remains challenging. The ST2R technique supported significant triplanar corrections, including TK apex translocation and restoration of hypokyphosis in most patients. Comparisons with the RR cohort require caution because of differences in the implant profile. However, ST2R significantly improved the coronal and sagittal corrections. It also allowed for distribution of correctional forces over two rod implants instead of one, which should decrease the risk of screw pullout and rod flattening. It is hoped that the description here of commercially available reducers used with the authors' surgical technique will encourage other clinicians to consider using the ST2R technique.

Rubinstein-Taybi syndrome with scoliosis treated with single-stage posterior spinal fusion: illustrative case.

BACKGROUND: Rubinstein-Taybi syndrome (RTS) is a rare disorder with a range of congenital anomalies. Although 40% to 60% of patients with RTS have scoliotic deformities, few reports discuss the outcomes of correctional surgery and postoperative care. To raise awareness of the clinical features of RTS and surgical considerations, the authors report on the surgical treatment of a pediatric patient with RTS accompanied by scoliosis. OBSERVATIONS: A 14-year-old girl with RTS presented with low back pain associated with progressive scoliosis. Because of jaw hypoplasia, videolaryngoscopy-mediated intubation was chosen. A single-stage T4-L3 posterior corrective fusion with instrumentation was successfully performed. Physical and imaging findings were analyzed up to 2 years after correction. The main thoracic Cobb angle was corrected from 73° to 12° and maintained for 2 years after surgery. The patient's low back pain resolved. LESSONS: Careful consideration of RTS-associated complications and preoperative planning, including the use of videolaryngoscopy-mediated intubation, anesthesia selection, and postoperative care, proved crucial. Scoliosis may appear in many variations in rare diseases such as RTS. Publication of case reports such as this one is needed to provide detailed information about strategies and considerations for correcting scoliotic deformities in patients with RTS.