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Although discectomy is commonly performed for lumbar intervertebral disc (IVD) herniation, the capacity for tissue repair after surgery is limited, resulting in residual lower back pain, recurrence of IVD herniation, and progression of IVD degeneration. Cell-based therapies, as one-step procedures, are desirable for enhancing IVD repair. This study aimed to investigate the therapeutic efficacy of a combination of newly developed ultra-purified alginate (UPAL) gel and bone marrow aspirate concentrate (BMAC) implantation for IVD repair after discectomy. Prior to an in vivo study, the cell concentration abilities of three commercially available preparation kits for creating the BMAC were compared by measuring the number of bone marrow mesenchymal stem cells harvested from the bone marrow of rabbits. Subsequently, canine-derived BMAC was tested in a canine model using a kit which had the highest concentration rate. At 24 weeks after implantation, we evaluated the changes in the magnetic resonance imaging (MRI) signals as well as histological degeneration grade and immunohistochemical analysis results for type II and type I collagen-positive cells in the treated IVDs. In all quantitative evaluations, such as MRI and histological and immunohistochemical analyses of IVD degeneration, BMAC-UPAL implantation significantly suppressed the progression of IVD degeneration compared to discectomy and UPAL alone. This preclinical proof-of-concept study demonstrated the potential efficacy of BMAC-UPAL gel as a therapeutic strategy for implementation after discectomy, which was superior to UPAL and discectomy alone in terms of tissue repair and regenerative potential.

Whether diurnal variation exists in quantitative MRI indices such as the T1rho relaxation time (T1ρ) of the intervertebral disc (IVD) is yet to be explored. This prospective study aimed to evaluate the diurnal variation in T1ρ, apparent diffusion coefficient (ADC), and electrical conductivity (σ) of lumbar IVD and its relationship with other MRI or clinical indices. Lumbar spine MRI, including T1ρ imaging, diffusion-weighted imaging (DWI), and electric properties tomography (EPT), was conducted on 17 sedentary workers twice (morning and evening) on the same day. The T1ρ, ADC, and σ of IVD were compared between the time points. Their diurnal variation, if any, was tested for correlation with age, body mass index (BMI), IVD level, Pfirrmann grade, scan interval, and diurnal variation in IVD height index. The results showed a significant decrease in T1ρ and ADC and a significant increase in the σ of IVD in the evening. T1ρ variation had a weak correlation with age and scan interval, and ADC variation with scan interval. Diurnal variation exists for the T1ρ, ADC, and σ of lumbar IVD, which should be accounted for in image interpretation. This variation is thought to be due to diurnal variations in intradiscal water, proteoglycan, and sodium ion concentration.

Abstract Patients with ossification of the ligamentum flavum (OLF) in the lumbar spine may be at high risk of developing concomitant ossification of the entire spinal ligament, but the etiology remains unclear. We investigated the propensity for spinal ligament ossification in asymptomatic subjects with lumbar OLF using the data of 595 Japanese individuals receiving medical check-ups, including computed tomography (CT) scanning. The severity of OLF (total number of intervertebral segments with OLF) of the entire spine on CT was quantified using an OLF index. Subjects with OLF were grouped according to this index: localized OLF (n = 138), intermediate OLF (n = 70), and extensive OLF (n = 31). The proportion of subjects with lumbar OLF increased with increasing OLF index (localized 13.7%, intermediate 41.4%, and extensive 70.9%). Multiple regression analysis found that lumbar OLF index was associated with thoracic OLF index, and co-existence of ossification of the posterior longitudinal ligament (OPLL) of the thoracic and lumbar spine. This study showed that subjects with more multilevel lumbar OLF were more likely to develop multilevel thoracic OLF and to have coexisting OPLL. Patients with lumbar OLF may be a distinctive subgroup with a strong tendency to ossification of the entire spinal ligament.

Abstract Obesity and metabolic disturbances are prevalent in ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF); however, the involvement of dyslipidemia (DL) in OPLL/OLF remains uncertain. We investigated the association between dyslipidemia and OPLL/OLF using a dataset of 458 individuals receiving health screening tests, including computed tomography. Subjects were grouped according to the presence or location of OPLL/OLF: controls (no OPLL/OLF, n = 230), OLF (n = 167), cervical OPLL (n = 28), and thoracic OPLL (n = 33). They were also grouped according to the presence of dyslipidemia (DL[+], n = 215; DL[−], n = 243). The proportion of dyslipidemia in the OLF and OPLL groups was 1.6–2.2 times higher than that in the control group. The proportion of OLF and OPLL in the DL(+) group was significantly higher than that in the DL(−) group (OLF, 43% vs. 29%; cervical OPLL, 14.4% vs. 3.2%; thoracic OPLL, 11.1% vs. 3.7%). Multivariate logistic regression analysis showed an association between all ossification types and dyslipidemia. This study demonstrated an association of dyslipidemia with OPLL/OLF; further investigation on the causal relationship between dyslipidemia and ectopic spinal ligament ossification is warranted to develop a therapeutic intervention for OPLL/OLF.

IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

The intervertebral disc (IVD) is a soft tissue that constitutes the spinal column together with the vertebrae, and consists of the central nucleus pulposus (gelatinous tissue) and the annulus fibrosus (rich in fibrous tissue) that surrounds the nucleus pulposus [...]

Introduction In patients with combined lumbar spinal canal stenosis (LSCS), a herniated intervertebral disc (IVD) that compresses the dura mater and nerve roots is surgically treated with discectomy after laminoplasty. However, defects in the IVD after discectomy may lead to inadequate tissue healing and predispose patients to the development of IVD degeneration. Ultrapurified stem cells (rapidly expanding clones (RECs)), combined with an in situ-forming bioresorbable gel (dMD-001), have been developed to fill IVD defects and prevent IVD degeneration after discectomy. We aim to investigate the safety and efficacy of a new treatment method in which a combination of REC and dMD-001 is implanted into the IVD of patients with combined LSCS.Methods and analysis This is a multicentre, prospective, double-blind randomised controlled trial. Forty-five participants aged 20–75 years diagnosed with combined LSCS will be assessed for eligibility. After performing laminoplasty and discectomy, participants will be randomised 1:1:1 into the combination of REC and dMD-001 (REC-dMD-001) group, the dMD-001 group or the laminoplasty and discectomy alone (control) group. The primary outcomes of the trial will be the safety and effectiveness of the procedure. The effectiveness will be assessed using visual analogue scale scores of back pain and leg pain as well as MRI-based estimations of morphological and compositional quality of the IVD tissue. Secondary outcomes will include self-assessed clinical scores and other MRI-based estimations of compositional quality of the IVD tissue. All evaluations will be performed at baseline and at 1, 4, 12, 24 and 48 weeks after surgery.Ethics and dissemination This study was approved by the ethics committees of the institutions involved. We plan to conduct dissemination of the outcome data by presenting our data at national and international conferences, as well as through formal publication in a peer-reviewed journal.Trial registration number jRCT2013210076.

Intervertebral disc (IVD) degeneration (IDD), a highly prevalent pathological condition worldwide, is widely associated with back pain. Treatments available compensate for the impaired function of the degenerated IVD but typically have incomplete resolutions because of their adverse complications. Therefore, fundamental regenerative treatments need exploration. Mesenchymal stem cell (MSC) therapy has been recognized as a mainstream research objective by the World Health Organization and was consequently studied by various research groups. Implanted MSCs exert anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects and promote extracellular component production, as well as differentiation into IVD cells themselves. Hence, the ultimate goal of MSC therapy is to recover IVD cells and consequently regenerate the extracellular matrix of degenerated IVDs. Notably, in addition to MSC implantation, healthy nucleus pulposus (NP) cells (NPCs) have been implanted to regenerate NP, which is currently undergoing clinical trials. NPC-derived exosomes have been investigated for their ability to differentiate MSCs from NPC-like phenotypes. A stable and economical source of IVD cells may include allogeneic MSCs from the cell bank for differentiation into IVD cells. Therefore, multiple alternative therapeutic options should be considered if a refined protocol for the differentiation of MSCs into IVD cells is established. In this study, we comprehensively reviewed the molecules, scaffolds, and environmental factors that facilitate the differentiation of MSCs into IVD cells for regenerative therapies for IDD.

Abstract Some surgical strategies can maintain or restore thoracic kyphosis (TK); however, next-generation surgical schemes for adolescent idiopathic scoliosis (AIS) should consider anatomical corrections. A four-dimensional correction could be actively achieved by curving the rod. Thus, anatomically designed rods have been developed as notch-free, pre-bent rods for easier anatomical reconstruction. This study aimed to compare the initial curve corrections obtained using notch-free rods and manually bent, notched rods for the anatomical reconstruction of thoracic AIS. Two consecutive series of 60 patients who underwent anatomical posterior correction for main thoracic AIS curves were prospectively followed up. After multilevel facetectomy, except for the lowest instrumented segment, either notch-free or notched rods were used. Patient demographic data, radiographic measurements, and sagittal rod angles were analyzed within 1 week after surgery. Patients with notch-free rods had significantly higher postoperative TK than patients with notched rods (P

Background and Objectives: Although full endoscopic lumbar discectomy with the transforaminal approach (FED-TF) is a minimally invasive spinal surgery for lumbar disc herniation, the lumbosacral levels present anatomical challenges when performing FED-TF surgery due to the presence of the iliac bone. Materials and Methods: In this study, we simulated whether FED-TF surgery could be safely performed on a total of 52 consecutive cases with L5–S1 or L5–L6 disc herniation using fused three-dimensional (3D) images of the lumbar nerve root on magnetic resonance imaging (MRI) created with artificial intelligence and of the lumbosacral spine and iliac on computed tomography (CT) images. Results: Thirteen of the fifty-two cases were deemed operable according to simulated FED-TF surgery without foraminoplasty using the 3D MRI/CT fusion images. All 13 cases underwent FED-TF surgery without neurological complications, and their clinical symptoms significantly improved. Conclusions: Three-dimensional simulation may allow for the assessment from multiple angles of the endoscope entry and path, as well as the insertion angle. FED-TF surgery simulation using 3D MRI/CT fusion images could be useful in determining the indications for full endoscopic surgery for lumbosacral disc herniation.

Abstract Lumbar intervertebral disc (IVD) herniation causes severe low back pain (LBP), which results in substantial financial and emotional strains. Despite the effectiveness of discectomy, there is no existing treatment for post-operative LBP induced by progressive IVD degeneration. Two key factors of LBP are intradiscal inflammation, indicated by tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and sensory nerve ingrowth into the inner layer of the annulus fibrosus, triggered by nerve growth factor/high-affinity tyrosine kinase A (TrkA) signalling. In an animal models of discectomy, the bioresorbable ultra-purified alginate (UPAL) gel with an extremely low-toxicity has been effective in acellular tissue repair. We aimed to investigate whether UPAL gel can alleviate LBP using a rat nucleus pulposus (NP) punch model and a rabbit NP aspirate model. In both models, we assessed TNF-α and IL-6 production and TrkA expression within the IVD by immunohistochemistry. Further, histological analysis and behavioural nociception assay were conducted in the rat model. UPAL gel implantation suppressed TNF-α and IL-6 production, downregulated TrkA expression, inhibited IVD degeneration, and reduced nociceptive behaviour. Our results suggest the potential of UPAL gel implantation as an innovative treatment for IVD herniation by reducing LBP and preventing IVD degeneration after discectomy.

Summary: Background: Lumbar intervertebral disc (IVD) herniations are associated with significant disability. Discectomy is the conventional treatment option for IVD herniations but causes a defect in the IVD, which has low self-repair ability, thereby representing a risk of further IVD degeneration. An acellular, bioresorbable, and good manufacturing practice (GMP)-compliant in situ-forming gel, which corrects discectomy-associated IVD defects and prevents further IVD degeneration had been developed. However, this acellular matrix-based strategy has certain limitations, particularly in elderly patients, whose tissues have low self-repair ability. The aim of this study was to investigate the therapeutic efficacy of using a combination of newly-developed, ultra-purified, GMP-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs) and the gel for IVD regeneration after discectomy in a sheep model of severe IVD degeneration. Methods: RECs and nucleus pulposus cells (NPCs) were co-cultured in the gel. In addition, RECs combined with the gel were implanted into IVDs following discectomy in sheep with degenerated IVDs. Findings: Gene expression of NPC markers, growth factors, and extracellular matrix increased significantly in the co-culture compared to that in each mono-culture. The REC and gel combination enhanced IVD regeneration after discectomy (up to 24 weeks) in the severe IVD degeneration sheep model. Interpretation: These findings demonstrate the translational potential of the combination of RECs with an in situ-forming gel for the treatment of herniations in degenerative human IVDs. Funding: Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue repair and reduces discogenic pain, and a combination of ultra-purified, Good Manufacturing Practice (GMP)-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs), and the UPAL gel increasingly enhanced IVD regeneration in animal models. This study investigated the therapeutic efficacy of injecting a mixture of REC and UPAL non-gelling solution for discogenic pain and IVD regeneration in a rat caudal nucleus pulposus punch model. REC and UPAL mixture and UPAL alone suppressed not only the expression of TNF-α, IL-6, and TrkA (p < 0.01, respectively), but also IVD degeneration and nociceptive behavior compared to punching alone (p < 0.01, respectively). Furthermore, REC and UPAL mixture suppressed these expression levels and nociceptive behavior compared to UPAL alone (p < 0.01, respectively). These results suggest that this minimally invasive treatment strategy with a single injection may be applied to treat discogenic pain and as a regenerative therapy.

An optimal surgical strategy for adolescent idiopathic scoliosis (AIS) is to provide maximal deformity correction while preserving spinal mobile segments as much as possible and obtaining a balanced posture. From a spatiotemporal deformity correction standpoint, we recently showed that anatomical four-dimensional (4D) spinal correction could be accomplished by curving the rod. In the surgical procedure, two rods are bent identically to confirm spinal anatomical alignment without referring to the intraoperative alignment of the deformity. Therefore, anatomically designed rods have been developed as notch-free, pre-bent rods for easier anatomical reconstruction. In addition to providing the best spinal instrumentation configurations as pre-bent rods, prediction of surgical outcome along with its biomechanical impact can be obtained by simulation of the surgical procedures with computer modeling. However, an objective model that can simulate the surgical outcome in patients with AIS has not been completely elucidated. The present study aimed to compare simulated deformity corrections based on our newly developed spatiotemporal morphological 4D planning simulation system incorporating pre-bent rods and actual deformity corrections in patients with AIS. A consecutive series of 47 patients who underwent anatomical posterior correction for AIS curves were prospectively evaluated. After multilevel facetectomy, except for the lowest instrumented segment, 11 types of pre-bent rods were used. Patient demographic data, radiographic measurements, and sagittal rod angles were analyzed within 1 week of surgery. Our simulation system incorporating pre-bent rods showed a significant correlation with the actual postoperative spinal alignment. The present study demonstrated the feasibility of our simulation system and the ability to simulate the surgical procedure using the pre-bent rods. The simulation system can be used to minimize the differences between the optimal and possible outcomes related to the instrumentation levels and rod shapes. Preoperative assumption of rod shape and length can contribute to a reduction in operative time which decreases blood loss and risk of infection. The results of the finite element analysis in the simulation system measured for each individual patient would also provide a more realistic representation of the surgical procedures.

Herniated nucleus pulposus (NP), one of the most common diseases of the spine, is surgically treated by removing the sequestered NP. However, intervertebral disc (IVD) defects may remain after discectomy, leading to inadequate tissue healing and predisposing patients to IVD degeneration. An acellular, bioresorbable, ultra-purified alginate (UPAL) gel (dMD-001) implantation system can be used to fill any IVD defects in order to prevent IVD degeneration after discectomy. This first-in-human pilot study aims to determine the feasibility, safety, and perceived patient response to a combined treatment involving discectomy and UPAL gel implantation for herniated NP. We designed a one-arm, double-centre, open-label, pilot trial. The study started in November 2018 and will run until a sample of 40 suitable participants is established. Patients aged 20–49 years, diagnosed with isolated lumbar IVD herniation and scheduled for discectomy represent suitable candidates. All eligible participants who provide informed consent undergo standard discectomy followed by UPAL gel implantation. The primary outcomes of the trial will be the feasibility and safety of the procedure. Secondary outcomes will include self-assessed clinical scores and magnetic resonance imaging-based measures of morphological and compositional quality of the IVD tissue. Initial outcomes will be published at 24 weeks. Analysis of feasibility and safety will be performed using descriptive statistics. Both intention-to-treat and per-protocol analyses of treatment trends of effectiveness will be conducted.

Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.

Study Design Retrospective case-control study, level 4. Purpose To clarify the risk factors for late subaxial lesion after occipitocervical (O-C) reconstruction. We examined cases requiring fusion-segment-extended (FE) reconstruction in addition to/after O-C reconstruction. Overview of Literature Patients with rheumatoid arthritis (RA) frequently require O-C reconstruction surgery for cranio-cervical lesions. Acceptable outcomes are achieved via indirect decompression using cervical pedicle screws and occipital plate–rod systems. However, late subaxial lesions may develop occasionally following O-C reconstruction. Methods O-C reconstruction using cervical pedicle screws and occipital plate–rod systems was performed between 1994 and 2007 in 113 patients with RA. Occipito-atlanto-axial (O-C2) reconstruction was performed for 89 patients, and occipito-subaxial cervical (O-under C2) reconstruction was performed for 24 patients. We reviewed the cases of patients requiring FE reconstruction (fusion extended group, FEG) and 26 consecutive patients who did not require FE reconstruction after a follow-up of >5 years (non-fusion extended group, NEG) as controls. Results FE reconstructions were performed for nine patients at an average of 45 months (range, 24–180 months) after O-C reconstruction. Of the 89 patients, three (3%) underwent FE reconstruction in cases of O-C2 reconstruction. Of the 24 patients, five (21%) underwent FE reconstruction in cases of O-under C2 reconstruction (p=0.003, Fisher exact test). Age, sex, RA type, and neurological impairment stage were not significantly different between FEG and NEG. O-under C2 reconstruction, larger correction angle (4° per number of unfixed segment), and O-C7 angle change after O-C reconstruction were the risk factors for late subaxial lesions on radiographic assessment. Conclusions Overcorrection of angle at fusion segments requiring O-C7 angle change was a risk factor for late subaxial lesion in patients with RA with fragile bones and joints. Correction should be limited, considering the residual mobility of the cervical unfixed segments.

Background: Because the regenerative ability of intervertebral discs (IVDs) is restricted, defects caused by discectomy may induce insufficient tissue repair leading to further IVD degeneration. An acellular bioresorbable biomaterial based on ultra-purified alginate (UPAL) gel was developed to fill the IVD cavity and prevent IVD degeneration. However, an acellular matrix-based strategy may have limitations, particularly in the elderly population, who exhibit low self-repair capability. Therefore, further translational studies involving product combinations, such as UPAL gel plus bone marrow-derived mesenchymal stem cells (BMSCs), are required to evaluate the regenerative effects of BMSCs embedded in UPAL gel on degenerated IVDs. Methods: Rabbit BMSCs and nucleus pulposus cells (NPCs) were co-cultured in a three-dimensional (3D) system in UPAL gel. In addition, rabbit or human BMSCs combined with UPAL gel were implanted into IVDs following partial discectomy in rabbits with degenerated IVDs. Findings: Gene expression of NPC markers, growth factors, and extracellular matrix was significantly increased in the NPC and BMSC 3D co-culture compared to that in each 3D mono-culture. In vivo, whereas UPAL gel alone suppressed IVD degeneration as compared to discectomy, the combination of BMSCs and UPAL gel exerted a more potent effect to induce IVD regeneration. Similar IVD regeneration was observed using human BMSCs. Interpretation: These findings demonstrate the therapeutic potential of BMSCs combined with UPAL gel as a regenerative strategy following discectomy for degenerated IVDs. Funding: Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd. Keywords: Intervertebral disc, Herniated disc, Bone marrow mesenchymal stem cell, Biomaterial

BackgroundAdolescent idiopathic scoliosis (AIS) patients typically undergo surgical treatment as teenagers, follow-ups of >5 years are necessary to evaluate effects on peak pulmonary reserves. However, limited data is available regarding the long-term (>10 years) effects of surgical intervention on pulmonary function (PF) in patients with thoracic AIS.ObjectiveTo provide long-term (>10 years) information on the PF after posterior spinal fusion for treating main thoracic AIS. We especially investigated whether surgical correction for AIS led to impairment of the PF.MethodsA total of 35 patients with main thoracic AIS treated with posterior spinal fusion were included. Radiographs and PF tests, which included measurements of absolute and percent-predicted values of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), were evaluated.ResultsMean age at surgery was 14.9 years (12-19 years). Mean follow-up period was 15.1 years (10-24 years). Although the final postoperative FVC and FEV1 absolute values were higher than the preoperative values, the differences were not statistically significant (p = 0.22 and p = 0.08, respectively). Percent-predicted FVC and FEV1 values between preoperative and final postoperative measurements were not statistically different (p = 0.63 and p = 0.29, respectively). However, for the patients who presented with pulmonary impairment preoperatively, both the FVC and FEV1 significantly increased at the final follow-up (p = 0.01 and p = 0.01, respectively).ConclusionsLong-term results of AIS patients who underwent posterior spinal fusion in main thoracic curves demonstrated absolute and percent-predicted PF test values similar to preoperative measurements; thus, indicating that posterior spinal fusion did not decrease PF 15 years after the initial surgery. Instead, patients with severe preoperative pulmonary impairment might show some degree of improvement after surgery.

Intervertebral disc (IVD) degeneration is a common cause of low back pain and most spinal disorders. As IVD degeneration is a major obstacle to the healthy life of so many individuals, it is a major issue that needs to be overcome. Currently, there is no clinical treatment for the regeneration of degenerated IVDs. However, recent advances in regenerative medicine and tissue engineering suggest the potential of cell-based and/or biomaterial-based IVD regeneration therapies. These treatments may be indicated for patients with IVDs in the intermediate degenerative stage, a point where the number of viable cells decreases, and the structural integrity of the disc begins to collapse. However, there are many biological, biomechanical, and clinical challenges that must be overcome before the clinical application of these IVD regeneration therapies can be realized. This review summarizes the basic research and clinical trials literature on cell-based and biomaterial-based IVD regenerative therapies and outlines the important role of these strategies in regenerative treatment for IVD degenerative diseases, especially disc herniation.

Intervertebral disc degeneration (IVDD) is a pathological condition that can lead to intractable back pain or secondary neurological deficits. There is no fundamental cure for this condition, and current treatments focus on alleviating symptoms indirectly. Numerous studies have been performed to date, and the major strategy for all treatments of IVDD is to prevent cell loss due to programmed or regulated cell death. Accumulating evidence suggests that several types of cell death other than apoptosis, including necroptosis, pyroptosis, and ferroptosis, are also involved in IVDD. In this study, we discuss the molecular pathway of each type of cell death and review the literature that has identified their role in IVDD. We also summarize the recent advances in targeted therapy at the RNA level, including RNA modulations through RNA interference and regulation of non-coding RNAs, for preventing cell death and subsequent IVDD. Therefore, we review the causes and possible therapeutic targets for RNA intervention and discuss the future direction of this research field.

Background: The current surgical procedure of choice for lumbar intervertebral disc (IVD) herniation is discectomy. However, defects within IVD produced upon discectomy may impair tissue healing and predispose patients to subsequent IVD degeneration. This study aimed to investigate whether the use of an acellular bioresorbable ultra-purified alginate (UPAL) gel implantation system is safe and effective as a reparative therapeutic strategy after lumbar discectomy. Methods: Human IVD cells were cultured in a three-dimensional system in UPAL gel. In addition, lumbar spines of sheep were used for mechanical analysis. Finally, the gel was implanted into IVD after discectomy in rabbits and sheep in vivo. Findings: The UPAL gel was biocompatible with human IVD cells and promoted extracellular matrix production after discectomy, demonstrating sufficient biomechanical characteristics without material protrusion. Interpretation: The present results indicate the safety and efficacy of UPAL gels in a large animal model and suggest that these gels represent a novel therapeutic strategy after discectomy in cases of lumbar IVD herniation. Fund: Grant-in-Aid for the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd. Keywords: Intervertebral disc, Biomaterials, Biomechanics, Tissue engineering

Flattening of the preimplantation rod contour in the sagittal plane influences thoracic kyphosis (TK) restoration in adolescent idiopathic scoliosis (AIS) surgery. The effects of multilevel facetectomy and screw density on postoperative changes in spinal rod contour have not been documented. This study aimed to evaluate the effects of multilevel facetectomy and screw density on changes in spinal rod contour from before implantation to after surgical correction of thoracic curves in patients with AIS prospectively. The concave and convex rod shapes from patients with thoracic AIS (n = 49) were traced prior to insertion. Postoperative sagittal rod shape was determined by computed tomography. The angle of intersection of the tangents to the rod end points was measured. Multiple stepwise linear regression analysis was used to identify variables independently predictive of change in rod contour (Δθ). Average Δθ at the concave and convex side were 13.6° ± 7.5° and 4.3° ± 4.8°, respectively. The Δθ at the concave side was significantly greater than that of the convex side (P < 0.0001) and significantly correlated with Risser sign (P = 0.032), the preoperative main thoracic Cobb angle (P = 0.031), the preoperative TK angle (P = 0.012), and the number of facetectomy levels (P = 0.007). Furthermore, a Δθ at the concave side ≥14° significantly correlated with the postoperative TK angle (P = 0.003), the number of facetectomy levels (P = 0.021), and screw density at the concave side (P = 0.008). Rod deformation at the concave side suggests that corrective forces acting on that side are greater than on the convex side. Multilevel facetectomy and/or screw density at the concave side have positive effects on reducing the rod deformation that can lead to a loss of TK angle postoperatively.

Although human intervertebral disc degeneration can lead to several spinal diseases, its pathogenesis remains unclear. This study aimed to create a new histological classification applicable to an in vivo mouse intervertebral disc degeneration model induced by needle puncture. One hundred six mice were operated and the L4/5 intervertebral disc was punctured with a 35- or 33-gauge needle. Micro-computed tomography scanning was performed, and the punctured region was confirmed. Evaluation was performed by using magnetic resonance imaging and histology by employing our classification scoring system. Our histological classification scores correlated well with the findings of magnetic resonance imaging and could detect degenerative progression, irrespective of the punctured region. However, the magnetic resonance imaging analysis revealed that there was no significant degenerative intervertebral disc change between the ventrally punctured and non-punctured control groups. To induce significant degeneration in the lumbar intervertebral discs, the central or dorsal region should be punctured instead of the ventral region.

BACKGROUND: Discography and discoblock are imaging procedures used to diagnose discogenic low back pain. Although needle puncture of the intervertebral disc (IVD) itself induces disc degeneration, the agents used in these procedures may also have harmful effects on IVD cells. The purpose of this study was to analyze whether radiocontrast agents and local anesthetic agents have detrimental effects on human nucleus pulposus (NP) cells. METHODS: Healthy human NP cells were cultured for 7 days in three-dimensional (3D) cell-alginate bead composites, and were then exposed to clinically relevant doses of a radiocontrast agent (iotrolan) or local anesthetic (lidocaine or bupivacaine). Cell viability and apoptosis were measured by confocal microscopy and flow cytometry. On the basis of caspase expression profiles, the apoptotic pathways activated by the agents were identified by Western blot analysis. RESULTS: The radiocontrast agent iotrolan did not affect NP cell viability or induce apoptosis. In contrast, both the anesthetic agents significantly decreased cell viability and increased the apoptotic cell number in a time- and dose-dependent manner. After 120 min, 2% lidocaine and 0.5% bupivacaine decreased percent live cells to 13% and 10%, respectively (p

Analgesic discography (discoblock) can be used to diagnose or treat discogenic low back pain by injecting a small amount of local anesthetics. However, recent in vitro studies have revealed cytotoxic effects of local anesthetics on intervertebral disc (IVD) cells. Here we aimed to investigate the deteriorative effects of lidocaine and bupivacaine on rabbit IVDs using an organotypic culture model and an in vivo long-term follow-up model.For the organotypic culture model, rabbit IVDs were harvested and cultured for 3 or 7 days after intradiscal injection of local anesthetics (1% lidocaine or 0.5% bupivacaine). Nucleus pulposus (NP) cell death was measured using confocal microscopy. Histological and TUNEL assays were performed. For in vivo study, each local anesthetic was injected into rabbit lumbar IVDs under a fluoroscope. Six or 12 months after the injection, each IVD was prepared for magnetic resonance imaging (MRI) and histological analysis.In the organotypic culture model, both anesthetic agents induced time-dependent NP cell death; when compared with injected saline solution, significant effects were detected within 7 days. Compared with the saline group, TUNEL-positive NP cells were significantly increased in the bupivacaine group. In the in vivo study, MRI analysis did not show any significant difference. Histological analysis revealed that IVD degeneration occurred to a significantly level in the saline- and local anesthetics-injected groups compared with the untreated control or puncture-only groups. However, there was no significant difference between the saline and anesthetic agents groups.In the in vivo model using healthy IVDs, there was no strong evidence to suggest that discoblock with local anesthetics has the potential of inducing IVD degeneration other than the initial mechanical damage of the pressurized injection. Further studies should be performed to investigate the deteriorative effects of the local injection of analgesic agents on degenerated IVDs.

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P=4.00 × 10(-8), odds ratio [OR]=2.05). Its association was replicated in a Chinese population (combined P=6.43 × 10(-12), OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.

BACKGROUND: Intervertebral disc degeneration is a significant cause of degenerative spinal diseases. Nucleus pulposus (NP) cells reportedly fail to survive in large degenerated discs with limited nutrient availability. Therefore, understanding the regulatory mechanism of the molecular response of NP cells to nutrient deprivation may reveal a new strategy to treat disc degeneration. This study aimed to identify genes related to nutrient deprivation in NP cells on a global scale in an experimental nutrient deprivation model. METHODOLOGY/PRINCIPAL FINDINGS: Rat NP cells were subjected to serum starvation. Global gene expression was profiled by microarray analysis. Confirmation of the selected genes was obtained by real-time polymerase chain reaction array analysis. Western blotting was used to confirm the expression of selected genes. Functional interactions between p21(Cip1) and caspase 3 were examined. Finally, flow cytometric analyses of NP cells were performed. Microarray analysis revealed 2922 differentially expressed probe sets with ≥1.5-fold changes in expression. Serum starvation of NP cells significantly affected the expression of several genes involved in DNA damage checkpoints of the cell cycle, including Atm, Brca1, Cdc25, Gadd45, Hus1, Ppm1D, Rad 9, Tp53, and Cyclin D1. Both p27(Kip1) and p53 protein expression was upregulated in serum-starved cells. p21(Cip1) expression remained in NP cells transfected with short interfering RNA targeting caspase 3 (caspase 3 siRNA). Both G1 arrest and apoptosis induced by serum starvation were inhibited in cells transfected with caspase 3 siRNA. CONCLUSIONS/SIGNIFICANCE: Nutrient deprivation in NP cells results in the activation of a signaling response including DNA damage checkpoint genes regulating the cell cycle. These results provide novel possibilities to improve the success of intervertebral disc regenerative techniques.