Intervertebral Disc Degeneration Research Articles

Correlation Between Osteoporosis and Endplate Damage in Degenerative Disc Disease Patients: A Study Based on Phantom-Less Quantitative Computed Tomography and Total Endplate Scores

BackgroundOsteoporosis and degenerative disc disease (DDD) are prevalent in the elderly population. Damage to the vertebral endplate, which impairs nutrient supply to the disc, serves as both a significant initiator and a hallmark of DDD. This study was aimed to explore the association between osteoporosis and endplate damage. MethodsThis retrospective study included 205 patients with DDD who were treated at tianjin hospital from January 2019 to May 2023. We collected data on age, sex, body mass index (BMI), phantom-less quantitative computed tomography (PL-QCT) values, and total endplate scores (TEPS). The average PL-QCT value of L1-L4 and TEPS were used to represent volumetric bone mineral density (v-BMD) and the degree of endplate damage, respectively. Based on the average PL-QCT value of L1 and L2, patients were divided into three groups: normal group (BMD > 120 mg/cm3), osteopenic group (80 mg/cm3 ≤ BMD ≤ 120 mg/cm3), and osteoporosis group (BMD < 80 mg/cm3). Multiple linear regression models were used to identify independent factors associated with endplate damage. ResultsThe overall TEPS (4.3±1.3 vs 5.0±1.0 vs 5.9±1.5, p<0.01) and segment (L1/2-L4/5) TEPS (p<0.05) in each group showed significant difference (R=-0.5), increasing in order from normal group to osteoporosis group. A significant negative correlation was found between TEPS and PL-QCT values in overall and each segments (p<0.001). The PL-QCT values and age (p<0.05) were independent factors influencing endplate damage. There were significant differences in the average number of TEPS ≥7 segments per patient among the three groups, with 1.16, 0.41, and 0.2 segments/person from osteoporosis group to normal group. ConclusionsOur study showed a significant positive correlation between osteoporosis and endplate damage. Attention is warranted for patients with osteopenia to prevent progression to osteoporosis, potentially leading to exacerbated DDD. The management of patients with both DDD and osteoporosis necessitates comprehensive treatment strategies that address both the BMD and endplate aspects of these conditions.

Facile fabrication of nano-bioactive glass functionalized blended hydrogel with nucleus pulposus-derived MSCs to improve regeneration potential in treatment of disc degeneration by in vivo rat model

Orthopaedic medicine often treats intervertebral disc degeneration (IVDD), which is caused by nucleus pulposus (NP) tissue damage and mechanical stress. Bioactive glasses (BGs), widely used for bone regeneration, can incorporate therapeutic ions into their network. Manganese (Mn) activates human osteoblast integrins, proliferation, and spreading. The CMnBGNPs-NPMSCs are carboxymethyl cellulose hydrogels functionalized with MnBGsNPs and NP-derived mesenchymal stem cells to treat IVDD. To ensure stability and biocompatibility of CMnBGNPs-NPMSCs were characterized for rheological properties like gelation time and swelling ratio. Gene expression analysis of PAX1, FOXF1, CA12, HBB, and OVOS2 via qRT-PCR further assessed the hydrogel's characteristics. Rat models with induced IVDD had hydrogel-MSC composite injected into their intervertebral discs for in vivo studies. Histological examination, immunohistochemical staining for inflammation and disc regeneration markers, and disc height assessments assessed therapeutic efficacy. CMnBGNPs-NPMSCs show promising results for IVDD treatment, offering a novel therapeutic strategy with clinical implications for degenerative disc diseases.

LTF ameliorates cartilage endplate degeneration by suppressing calcification, senescence and matrix degradation through the JAK2/STAT3 pathway.

Intervertebral disc degeneration (IDD)-induced cervical and lumbar herniations are debilitating diseases. The function of intervertebral disc (IVD) mainly depends on the cartilage endplate (CEP), which provides support and waste removal. Therefore, IDD stems from the degeneration of CEP. Our study shows that the expression of lactotransferrin (LTF), an iron-binding protein, is significantly decreased in degenerated human and rat CEP tissues. In addition, we found that LTF knockdown promoted calcification, senescence, and extracellular matrix (ECM) degradation in human endplate chondrocytes. Furthermore, the invivo experiment results confirmed that the JAK2/STAT3 pathway inhibitor AG490 significantly reversed these effects. In addition to investigating the role and mechanism of LTF in CEP degeneration, this study provides a theoretical basis and experimental evidence to improve IDD treatment.

Revolutionizing Intervertebral Disc Regeneration: Advances and Future Directions in Three-Dimensional Bioprinting of Hydrogel Scaffolds.

Hydrogels are multifunctional platforms. Through reasonable structure and function design, they use material engineering to adjust their physical and chemical properties, such as pore size, microstructure, degradability, stimulus-response characteristics, etc. and have a variety of biomedical applications. Hydrogel three-dimensional (3D) printing has emerged as a promising technique for the precise deposition of cell-laden biomaterials, enabling the fabrication of intricate 3D structures such as artificial vertebrae and intervertebral discs (IVDs). Despite being in the early stages, 3D printing techniques have shown great potential in the field of regenerative medicine for the fabrication of various transplantable tissues within the human body. Currently, the utilization of engineered hydrogels as carriers or scaffolds for treating intervertebral disc degeneration (IVDD) presents numerous challenges. However, it remains an indispensable multifunctional manufacturing technology that is imperative in addressing the escalating issue of IVDD. Moreover, it holds the potential to serve as a micron-scale platform for a diverse range of applications. This review primarily concentrates on emerging treatment strategies for IVDD, providing an in-depth analysis of their merits and drawbacks, as well as the challenges that need to be addressed. Furthermore, it extensively explores the biological properties of hydrogels and various nanoscale biomaterial inks, compares different prevalent manufacturing processes utilized in 3D printing, and thoroughly examines the potential clinical applications and prospects of integrating 3D printing technology with hydrogels.

Sex-specific divergences in the types and timing of infiltrating immune cells during the intervertebral disc acute injury response and their associations with degeneration

ObjectiveInadequate repair of the intervertebral disc (IVD) contributes to low back pain. Infiltrating immune cells into damaged tissues are critical mediators of repair, yet little is known about the identities, roles, and temporal regulation following IVD injury. By analyzing transcripts of immune cell markers, histopathologic analysis, immunofluorescence, and flow cytometry, we aimed to define the temporal cascade of infiltrating immune cells and their associations with IVD degeneration. MethodCaudal IVDs from 12-week old C57BL/6 mice were injured and monitored for 42-days post injury. Transcriptional markers identifying myeloid, B, and T immune cells, and angiogenic factors were measured in the IVDs every 2-3 days. Histopathologic degeneration of the IVD was measured throughout. Flow cytometry and immunofluorescence was used to identify and localize cells including the B, T, NKT, monocytes, neutrophils, macrophages, and dendritic cells. ResultsThe injured IVD revealed distinct phases of inflammation and proliferation. Robust temporal oscillation in the myeloid and T cell transcripts was observed in females. Cd3+ T cells were more abundant in females than in males. The Cd3+Cd4-Cd8- T cells that dominate the female cascade contain rare γδ T cells. Injury-mediated degeneration was prevalent in both sexes but more severe in males. ConclusionsThis study defines the coordinated infiltration of immune cells in the IVD following injury. We report the discovery of γδ T cells in the female IVD and this was associated with less severe degeneration. γδ T cells have potent anti-inflammatory roles and may suppress degeneration following IVD injury.

Exosomes Derived from Rejuvenated Stem Cells Inactivate NLRP3 Inflammasome and Pyroptosis of Nucleus Pulposus Cells via the Transfer of Antioxidants.

Accumulating evidence supports the potential of exosomes as a promising therapeutic approach for intervertebral disc degeneration (IDD). Nevertheless, enhancing the efficiency of exosome treatment remains an urgent concern. This study investigated the impact of quercetin on the characteristics of mesenchymal stem cells (MSCs) and their released exosomes. Exosomes were obtained from quercetin pre-treated MSCs and quantified for the production based on nanoparticle tracking and western blot analysis. The molecules involved in the secretion and cargo sorting of exosomes were investigated using western blot and immunofluorescence analysis. Based on the in vitro biological analysis and in vivo histological analysis, the effects of exosomes derived from conventional or quercetin-treated MSCs on nucleus pulposus (NP) cells were compared. A significant enhancement in the production and transportation efficiency of exosomes was observed in quercetin-treated MSCs. Moreover, the exosomes derived from quercetin-treated MSCs exhibited a greater abundance of antioxidant proteins, specifically superoxide dismutase 1 (SOD1), which inhibit the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome in NP cells. Through in vitro and in vivo experiments, it was elucidated that exosomes derived from quercetin-treated MSCs possessed enhanced anti-inflammatory and antioxidant properties. Collectively, our research underscores an optimized therapeutic strategy for IDD utilizing MSC-derived exosomes, thereby augmenting the efficacy of exosomes in intervertebral disc regeneration.

Effects of hydrostatic pressure, osmotic pressure, and confinement on extracellular matrix associated responses in the nucleus pulposus cells ex vivo

Spinal movement in both upright and recumbent positions generates changes in physicochemical stresses including hydrostatic pressure (HP), deviatoric stress, and confinement within the intradiscal compartment. The nucleus pulposus (NP) of the intervertebral disc is composed of highly negatively charged extracellular matrix (ECM), which increases osmotic pressure (OP) and generates tissue swelling. In pursuing regenerative therapies for intervertebral disc degeneration, the effects of HP on the cellular responses of NP cells and the ECM environment remain incompletely understood. We hypothesized that anabolic turnover of ECM in NP tissue is maintained under HP and confinement. We first clarified the effects of the relationships among HP, OP, and confinement on swelling NP explants isolated from bovine caudal intervertebral discs over 12 hours. We found that the application of confinement and constant HP significantly inhibits the free swelling of NP (p < 0.01) and helps retain the sulfated glycosaminoglycan. Since confinement and HP inhibited swelling, we incubated confined NPs under HP in high-osmolality medium mimicking ECM-associated OP for 7 days and demonstrated the effects of HP on metabolic turnover of ECM molecules in NP cells. The aggrecan core protein gene was significantly upregulated under confinement and constant HP compared to confinement and no HP (p < 0.01). We also found that confinement and constant HP helped to significantly retain smaller cell area (p < 0.01) and significantly prevent the severing of actin filaments compared to no confinement and HP (p < 0.01). Thus, we suggest that NP's metabolic turnover and cellular responses are regulated by the configuration of intracellular actin and fibrillar ECMs under HP.

Semaglutide exposure and its association with adverse outcomes in diabetic patients undergoing transforaminal lumbar interbody fusion for lumbar degenerative disc disease.

Semaglutide, a novel glucagon-like peptide-1 receptor agonist, has transformed the therapeutic landscape for type 2 diabetes mellitus. However, its effect on osteoclast activity and its potential to induce weight-related muscle loss raises concerns about its impact on spine surgery outcomes. As such, evaluating semaglutide's influence on transforaminal lumbar interbody fusion (TLIF) is imperative, given the procedure's reliance on successful bony fusion to prevent postoperative instability and further interventions. Using an all-payer database (MARINER), the authors analyzed data from patients with type 2 diabetes mellitus who were 18-74 years of age and who underwent short-segment fusion (≤ 3-level) TLIFs between January 2018 and October 2022. Patients were either exposed to semaglutide or not. A comprehensive 1:3 (exposure vs no exposure) matching was performed based on age, sex, obesity, hypertension, coronary artery disease, chronic kidney disease, smoking status, osteoporosis, levels of surgery, and basal-bolus insulin dependence. Kaplan-Meier survival curves and log-rank testing were performed to study the probability of additional lumbar fusion surgery within 1 year. After the 1:3 matching, 1781 patients were identified, with 447 in the semaglutide-exposed cohort and 1334 in the nonexposed cohort. Most patients in both groups were 55-69 years old, and 59.3% were female. Analysis showed that the likelihood of undergoing additional lumbar fusion surgery within 1 year post-TLIF was significantly higher in the semaglutide-exposed group than in the nonexposed group (OR 11.79, 95% CI 8.17-17.33). Kaplan-Meier plots and log-rank testing further confirmed a statistically significant divergent probability in the need for additional surgery within 1 year between the cohorts (log-rank, p < 0.001). Semaglutide exposure appears to be associated with a higher likelihood of additional lumbar fusion surgeries within 1 year post-TLIF, especially in patients receiving the medication for longer durations. Although the mechanisms remain speculative, potential impacts on bone turnover and the onset of muscle loss may be contributory factors. Further research is needed to elucidate the exact mechanisms and to develop strategies for optimizing surgical outcomes in these patients.

Risk factors of bone loss after Prestige-LP cervical disc arthroplasty.

Cervical disc arthroplasty (CDA) is widely employed for patients diagnosed with cervical degenerative disc disease (CDDD). Postoperative bone loss (BL) represents a radiological alteration that is a relatively novel consideration in the realm of CDA. This study endeavors to examine the risk factors associated with BL following CDA, aiming to elucidate the underlying mechanisms and the impact of BL on surgical outcomes. A retrospective study was undertaken, encompassing consecutive patients subjected to one-level CDA, two-level CDA, or two-level hybrid surgery (HS) for the treatment of CDDD at our institution. Patient demographic and perioperative data were systematically recorded. Radiological images obtained preoperatively, at 1-week post-operation, and during the last follow-up were collected and evaluated, following with statistical analyses. A total of 295 patients and 351 arthroplasty segments were involved in this study. Univariate logistic regressions indicated that age ≥ 45years and two-level HS was associated with lower risk of BL; and a greater ΔDA (change of disc angle before and after surgery) was correlated with an increased risk of BL. Multivariate logistic regression determined that two-level HS and greater ΔDA were independent preventative and risk factors for BL, respectively. Further analysis revealed that severe BL significantly elevated the risk of implant subsidence compared to non-BL and mild BL. This study posited bone remodeling and micromotion as potential underlying mechanisms of BL. Subsequent research endeavors should delve into the divergent mechanisms and progression observed between lower- and higher-grade BL, aiming to prevent potential adverse outcomes associated with severe BL.

Protein Kinase C and Matrix Metalloproteinases Expression Using Phorbol Myristate Acetate in Degenerative Intervertebral Disc Cells.

Degeneration of nucleus pulposus (NP) cells involves multiple factors. The relationship between the canonical Wnt/β-catenin signaling pathway and matrix metalloproteinases (MMPs) is important in cellular senescence. Protein kinase C (PKC), an intermediate of the non-canonical Wnt pathway stimulated by phorbol myristate acetate (PMA), possibly prevents NP cell senescence, although not yet demonstrated in human-based studies. This study aimed to investigate the effect of PMA stimulation on the non-canonical and canonical Wnt pathways and MMP expression in human NP cells to ascertain its inhibitory effects on the senescence of NP cells. Human disc tissues of Pfirrmann grades 1 and 2 were collected from patients during spinal surgery and subsequently cultured. Protein and ribonucleic acid (RNA) were isolated from NP cells treated with PMA (400 nM) for 24 hours. Expression of MMP1, MMP13, tissue inhibitor of matrix metalloproteinase 1 (TIMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), transient receptor potential vanilloid 4 (TRPV4), interleukin-6 (IL-6), and β-catenin were detected using western blot analysis. Messenger RNA (mRNA) expression of type II collagen and glycosaminoglycan (GAG) were analyzed using reverse transcription polymerase chain reaction. IL-6 and prostaglandin E2 (PGE2) levels were measured using enzyme-linked immunosorbent assay. Expression of PKC-δ (intermediate of the non-canonical Wnt pathway) and β-catenin (intermediate of the canonical Wnt pathway) was increased by PMA treatment. The mRNA levels of type II collagen and GAG increased; however, their protein levels were not altered. PMA treatment increased the expression of MMP1, TIMP1, ADAMTS5, IL-6, PGE2, and TRPV4; however, the expression of MMP13 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was unaltered. PMA activated PKC-δ, affecting the non-canonical Wnt pathway; however, its effect on β-catenin in the canonical Wnt pathway was limited. β-catenin activation through the TRPV4 channel led to increased expression of MMP1 and ADAMTS5 and that of IL-6 and PGE2 owing to NF-κB expression. Consequently, the degeneration of NP cells was not prevented.

Polyphenol-Mediated Adhesive and Anti-Inflammatory Double-Network Hydrogels for Repairing Postoperative Intervertebral Disc Defects.

Hydrogels have garnered tremendous attention for their applications in the repair of intervertebral disk (IVD) degeneration and postoperative IVD defects. However, it is still challenging to develop a hydrogel fulfilling the requirements for high mechanical properties, adhesive capability, biocompatibility, antibacterial properties, and anti-inflammatory performance. Herein, we report a multifunctional double-network (DN) hydrogel composed of physically cross-linked carboxymethyl chitosan (CMCS) and tannic acid (TA) networks as well as chemically cross-linked acrylamide (AM) networks, which integrates the properties of high strength, adhesion, biocompatibility, antimicrobial activity, and anti-inflammation for the repair of postoperative IVD defects. The treatment with CMCS/TA/PAM DN hydrogels can significantly decrease the levels of inflammatory cytokines and degeneration-related factors and upregulated collagen type II alpha 1. In addition, the hydrogels can effectively seal the annulus fibrosus defect, prevent nucleus pulposus degeneration, retain IVD height, and restore the biomechanical properties of the disc to some extent. This polyphenol-mediated DN hydrogel is promising for sealing IVD defects and preventing herniation after lumbar discectomy.

Integration of bioinformatics and multi-layered experimental validation reveals novel functions of acetylation-related genes in intervertebral disc degeneration

BackgroundThe molecular mechanisms underlying intervertebral disc degeneration (IDD) remain poorly understood. The purpose of this work is to elucidate key molecules and investigate the roles of acetylation-related RNAs and their associated pathways in IDD. MethodDatasets GSE70362 and GSE124272 were obtained from the Gene Expression Omnibus (GEO) and combined to investigate differentially expressed genes (DEGs) associated with acetylation in IDD patients compared to healthy controls. Critical genes were pinpointed by integrating GO, KEGG and PPI networks. Furthermore, CIBERSORTx analysis was used to investigate the differences in immune cell infiltration between different groups and the biological processes (BP), cellular components (CC) and molecular functions (MF) were calculated by GSEA and GSVA. In addition, The single-cell database GSE165722 was incorporated to validate the specific expression patterns of hub genes in cells and identify distinct cell subtypes. This provides a theoretical basis for a more in-depth understanding of the roles played by critical cell subtypes in the process of IDD. Subsequently, tissues from IVD with varying degrees of degeneration were collected to corroborate the key DEGs using western blot, RT-qPCR, and immunofluorescence staining. ResultsBy integrating various datasets and references, we identified a total of 1620 acetylation-related genes. These genes were subjected to a combined analysis with the DEGs from the databases included in this study, resulting in the discovery of 358 acetylation-related differentially expressed genes (ARDEGs). A comparative analysis with differentially expressed genes obtained from three databases yielded 19 ARDEGs. The PPI network highlighted the top 10 genes (IL1B, LAMP1, PPIA, SOD2, LAMP2, FBL, MBP, SELL, IRF1 and KHDRBS1) based on their protein interaction relationships. CIBERSORTx immune infiltration analysis revealed a moderate positive correlation between the gene IL1β and Mast.cells.activated, as well as a similar correlation between the gene IRF1 and Mast.cells.activated. Single-cell dataset was used to identify cell types and illustrate the distribution of hub genes in different cell types. The two cell types with the highest AUCell scores (Neutrophils and Monocytes) were further explored, leading to the subdivision of Neutrophils into two new cell subtypes: S100A9-type Neutrophils and MARCKS-type Neutrophils. Monocytes were labeled as HLA-DRA9-type Monocytes and IGHG3-type Monocytes. Finally, molecular biology techniques were employed to validate the expression of the top 10 hub genes. Among them, four genes (IL1β, SOD2, LAMP2, and IRF1) were confirmed at the gene level, while two (IL1β and SOD2) were validated at the protein level. ConclusionIn this study, we carried out a thorough analysis across three databases to identify and compare ARDEGs between IDD patients and healthy individuals. Furthermore, we validated a subset of these genes using molecular biology techniques on clinical samples. The identification of these differently expressed genes has the potential to offer new insights for diagnosing and treating IDD.

Use of two-point and six-point Dixon MRI for fat fraction analysis in the lumbar vertebral bodies and paraspinal muscles in healthy dogs: comparison with magnetic resonance spectroscopy.

Fatty degeneration of the vertebral bodies and paravertebral muscles is associated with the presence, severity, and prognosis of spinal disease such as intervertebral disc degeneration. Therefore, the fat fraction (FF) of the vertebral bodies and paraspinal muscles has been considered a potential biomarker for assessing the pathophysiology, progression, and treatment response of spinal disease. Magnetic resonance spectroscopy (MRS) is considered the reference standard for fat quantification; however, it has limitations of a long acquisition time and is technically demanding. Chemical shift-encoding water-fat imaging, called the Dixon method, has recently been applied for rapid fat quantification with high spatial resolution. However, the Dixon method has not been validated in veterinary medicine, and we hypothesized that the Dixon method would provide a comparable assessment of the FF to MRS but would be faster and easier to implement in dogs. In this prospective study, we assessed the FF of the lumbar vertebral bodies and paravertebral muscles from the first to sixth lumbar vertebrae using MRS, the two-point Dixon method (LAVA-FLEX), and the six-point Dixon method (IDEAL-IQ) and compared these techniques. The FFs of vertebral bodies and paravertebral muscles derived from LAVA-FLEX and IDEAL-IQ showed significant correlations and agreement with those obtained with MRS. In particular, the FFs obtained with IDEAL-IQ showed higher correlations and better agreement with those obtained with MRS than those derived by LAVA-FLEX. Both Dixon methods showed excellent intra- and interobserver reproducibility for FF analysis of the vertebral bodies and paraspinal muscles. However, the test-retest repeatability of vertebral body and paraspinal muscle FF analysis was low for all three sequences, especially for the paraspinal muscles. The results of this study showed that LAVA-FLEX and IDEAL-IQ have high reproducibility and that their findings were highly correlated with the FFs of the lumber vertebral bodies and paraspinal muscles determined by MRS in dogs. The FF analysis could be performed much more easily and quickly using LAVA-FLEX and IDEAL-IQ than using MRS. In conclusion, LAVA-FLEX and IDEAL-IQ can be used as routine procedures in spinal magnetic resonance imaging in dogs for FF analysis of the vertebral bodies and paraspinal muscles.

Protective effects of alpinetin against interleukin-1β-exposed nucleus pulposus cells: Involvement of the TLR4/MyD88 pathway in a cellular model of intervertebral disc degeneration

Intervertebral disc degeneration (IDD) causes a variety of symptoms such as low back pain, disc herniation, and spinal stenosis, which can lead to high social and economic costs. Alpinetin has an anti-inflammatory potential, but its effect on IDD is unclear. Herein, we investigated the effect of alpinetin on IDD. To mimic an in vitro model of IDD, nucleus pulposus cells (NPCs) were exposed to interleukin 1β (IL-1β). The viability of NPCs was assessed by CCK-8 assay. The expression of Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), aggrecan, collagen-2, and matrix metalloproteinase-3 (MMP-3) was examined by qRT-PCR and western blotting. The protein levels of B cell lymphoma-2 (Bcl-2), Bcl-2-associated protein X (Bax), and cleaved caspase-3 were scrutinized by western blotting. The flow cytometry assay was performed to assess apoptosis of NPCs. The contents of inflammatory factors were examined by ELISA kits. Results showed that alpinetin repressed IL-1β-tempted activation of the TLR4/MyD88 pathway and apoptosis in NPCs. Alpinetin alleviated IL-1β-tempted inflammatory responses and oxidative stress in NPCs. Moreover, alpinetin lessened IL-1β-tempted extracellular matrix (ECM) degeneration in NPCs by enhancing the expression of aggrecan and collagen-2 and reducing the expression of MMP-3. The effects of alpinetin on IL-1β-exposed NPCs were neutralized by TLR4 upregulation. In conclusion, alpinetin repressed IL-1β-tempted apoptosis, inflammatory responses, oxidative stress, and ECM degradation in NPCs through the inactivation of the TLR4/MyD88 pathway.

Hydrogel and Microgel Collaboration for Spatiotemporal Delivery of Biofactors to Awaken Nucleus Pulposus‐Derived Stem Cells for Endogenous Repair of Disc

AbstractDepletion of nucleus pulposus‐derived stem cells (NPSCs) is a major contributing factor to the attenuation of endogenous regenerative capacity in intervertebral disc degeneration (IVDD). Introducing a hydrogel drug delivery system is a potential strategy for counteracting endogenous cell depletion. The present study proposes a delivery platform for the spatiotemporal release of multiple drugs by combining sodium alginate hydrogels with gelatin microgels (SCGP hydrogels). The SCGP hydrogels facilitated the initial release of chondroitin sulfate (ChS) and the gradual release of an independently developed parathyroid hormone‐related peptide (P2). The combined action of these two small molecule drugs “awakened” the reserve NPSCs, mitigated cell damage induced by H2O2, significantly enhanced their biological activity, and promoted their differentiation toward nucleus pulposus cells. The mechanical and viscoelastic properties of the hydrogel are enhanced by physical and chemical dual cross‐linking to adapt to the loading environment of the degenerated disc. A rat IVDD model is used to validate that the SCGP hydrogel can significantly inhibit the progression of IVDD and stimulate the endogenous repair of IVDD. Therefore, the spatiotemporal differential drug delivery system of the SCGP hydrogel holds promise as a convenient and efficacious therapeutic strategy for minimally invasive IVDD treatment.

Association Between Cumulative G-force Exposure and Cervical Spine Degenerative Changes.

Fighter pilots work in a unique environment and are subject to high G-force loads under simultaneous head movements. Neck pain is reported to be a common health problem among fighter pilots leading to time lost flying and flight duty limitations. The present study aimed to find out if differences in early military flight career G-force exposure levels could increase the risk for degenerative changes in the cervical spine. The study population consisted of 56 20-year-old Finnish Air Force male fighter pilot cadets, who underwent MRI of the cervical spine at baseline and after 5 years. During follow-up, the G-force exposure was measured using the individual Fatigue Index (FI) recordings. The FI data were collected from each flight with BAE Hawks and is determined by the number of times certain levels of G-forces are exceeded during the flights. The incidence or progression of each degenerative change was compared to individual FI values using Pearson correlation coefficients. The pilots flew on average 220 (±21) hours with high performance aircraft during follow-up, resulting in an average FI of 1.98 (±0.47). A statistically significant progression was found in intervertebral disc (IVD) degeneration sum score with no correlation to corresponding FI values. A statistically significant increase was also found in the prevalence of IVD herniations with a negative correlation with FI values. Other degenerative cervical spine changes did not progress or did not correlate with corresponding FI values. The prevalence of IVD degeneration and IVD herniations increases in the early phases of fighter pilots' career. Only the incidence of IVD herniations correlated with FI values and the correlation was negative. The negative correlation may be attributed to avoidance behavior due to neck pain, which was not measured in our study, or other unmeasured confounding factors. This was the first study to compare individual G-force exposure levels to high-quality MRI data over a follow-up of several years. Finnish fighter pilots are known to report increasing cervical symptoms during the Hawk training phase, but longer follow-up periods are likely needed to determine the association between G-force exposure levels and cervical degenerative changes.

Bone graft substitutes used in anterior lumbar interbody fusion: a contemporary systematic review of fusion rates and complications.

Anterior lumbar interbody fusion (ALIF) uses a broad-footprint interbody cage designed to maximize fusion rates for treating degenerative disc disease. Bone graft substitutes are being increasingly utilized during ALIF to replace or supplement autologous iliac crest bone grafts. This approach aims to optimize fusion efficacy while minimizing associated postoperative complications. The objective of this systematic review was to examine recent studies on fusion rates and postoperative complications associated with bone graft substitutes used in ALIF. We conducted a systematic review of the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, MEDLINE, and PubMed databases, to critically examine a decade of research (January 1, 2012, to July 6, 2023) on the effectiveness and safety of various bone graft substitutes in ALIF. This timeframe was chosen to build on a previous systematic review published in 2013. The PRISMA guidelines were used. In total, 27 articles met our stringent inclusion and exclusion criteria. A substantial portion of these studies (67%) focused on recombinant human bone morphogenetic protein-2 (rhBMP-2) and highlighted its efficacy for achieving high fusion rates. However, the literature presents a dichotomy regarding the association of rhBMP-2 with increased postoperative complications. Notably, the methodologies for evaluating spinal fusion varied across studies. Only one-third of studies employed computed tomography to assess interbody fusion at 12 months postoperatively, highlighting the urgent need to establish uniform fusion criteria to facilitate more accurate comparative analyses. Moreover, there was considerable variability in the criteria used for diagnosing and detecting postoperative complications, significantly influencing the reported incidence rates. This review underscores the need for continued research into bone graft substitutes, particularly focusing on assessment of long-term complications. Future research endeavors should concentrate on developing comprehensive clinical guidelines to aid in the selection of the most suitable bone graft substitutes for use in ALIF, thereby enhancing patient outcomes and surgical efficacy.

Positive Cutibacterium acnes Intervertebral Discs Are Not Associated with Subsidence Following Anterior Cervical Discectomy and Fusion at 3 or 6 Months.

Background/Objectives:Cutibacterium acnes (C. acnes), formerly known as Propionibacterium acnes (P. acnes), is an anaerobic, low-virulent bacterium that has been associated with postoperative infections of the shoulder, knee, and cervical spine. Recent studies have highlighted an association between C. acnes and the development of degenerative disc disease (DDD). The aim of this study is to ascertain whether C. acnes increases the risk of subsidence following anterior cervical discectomy and fusion (ACDF). Methods: After IRB approval, consecutive patients undergoing elective ACDF for DDD from 2017 to 2018 were enrolled in this prospective cohort study. Intervertebral disc samples were taken at each affected level and cultured. A total of 66 patients with radiographic follow-ups were included in the final analysis. The extent of subsidence and cervical lordosis was determined immediately postoperatively and at the 3- and 6-month follow-ups. Results: No significant difference in subsidence was observed at 3 months (p = 0.07) or 6 months (p = 0.11) between culture-positive and -negative cohorts. Additionally, there was no significant difference detected in the change in cervical lordosis observed at 3 months (p = 0.16) or 6 months (p = 0.27) between culture-positive and -negative cohorts. For the most inferiorly fused segment, there was a significant difference in subsidence observed at 3 months (1.5 mm, 95% CI: 0.2-2.7 mm, p = 0.02) but not at 6 months (p = 0.17). Conclusions: Intervertebral discs with a positive C. acnes culture were not associated with greater levels of subsidence at 3 or 6 months following ACDF for DDD. Further research is necessary to endorse these results and to gauge the clinical significance of C. acnes infection.

Fibulin-3 Regulates Tissue Inhibitor of Metalloproteinases 3 to Inhibit Senescence in Intervertebral Disc Nucleus Pulposus Cells

To investigate the effect of fibulin-3 on the senescence of intervertebral disc nucleus pulposus cells (NPCs) through the regulation of tissue inhibitor of metalloproteinases 3 (TIMP-3) expression and to elucidate the molecular mechanisms involved. 1). The nucleus pulposus tissues and imaging data of 37 patients who had undergone intervertebral disc surgery were collected. The degree of degeneration of the intervertebral discs were classified according to the Pfirrmann grading system. The senescence degree of NPCs was determined using senescence-associated β-galactosidase (SA-β-gal) staining. Fibulin-3 expression levels were determined using Western blot and ELISA. The relationship between fibulin-3 and disc degeneration and NPCs senescence was investigated. 2). Human intervertebral disc NPCs were cultured in vitro. The proliferation and senescence of NPC across continuous passage were observed via CCK-8 assay and SA-β-gal staining, respectively. Fibulin-3 expression levels and the expression of inflammatory cytokines and matrix metalloproteinases were assessed. Exogenous fibulin-3 was added to verify its effect on the proliferation and senescence of NPCs. 3). The effect of fibulin-3 on the apoptosis and proliferation of NPCs was verified through gene overexpression, which was used in combination with an apoptosis inhibitor for bidirectional verification. 4). Bioinformatics analysis was performed to explore the relationship between fibulin-3 and the TIMP family. Experiments overexpressing fibulin-3 and silencing the TIMP-3 gene were performed to verify their role in NPCs senescence. 1). The intervertebral disc degeneration samples from 37 patients were classified according to the Pfirrmann grading system. The higher the degeneration grade, the lower fibulin-3 expression. Spearman correlation analysis showed that the disc grade was negatively correlated with the NPC senescence grade (r=－0.87, P<0.001) and fibulin-3 expression (r=－0.79, P<0.001). 2). As the passage number of NPCs increased, fibulin-3 expression gradually decreased, cell proliferation ability weakened, and the expression of inflammatory cytokines and matrix metalloproteinases increased. After exogenous fibulin-3 was added, cell morphology and growth status were maintained, cell senescence was significantly inhibited, and the expression of inflammatory cytokines and matrix metalloproteinases was markedly reduced. 3). Gene overexpression experiments showed that fibulin-3 reduced NPC apoptosis and promoted cell proliferation, thereby inhibiting NPC senescence. 4). Bioinformatics analysis revealed a significant association between fibulin-3 and TIMP-3 of the TIMP family. Further experiments confirmed that overexpressing fibulin-3 enhanced TIMP-3 expression, while silencing the TIMP-3 gene significantly weakened the inhibitory effect of fibulin-3 on NPCs senescence. This indicates that, through regulating TIMP-3, fibulin-3 inhibits the activity of matrix metalloproteinases, affects the synthesis and degradation of the extracellular matrix, and ultimately inhibits NPCs senescence. This study demonstrates that fibulin-3 plays a crucial role in inhibiting the senescence of intervertebral disc NPCs by regulating TIMP-3. The specific mechanisms involved are as follows, fibulin-3 upregulates TIMP-3 expression, inhibits matrix metalloproteinase activity, and reduces extracellular matrix degradation, thereby promoting extracellular matrix synthesis. Additionally, fibulin-3 inhibits NPCs senescence by reducing apoptosis and promoting cell proliferation. Therefore, fibulin-3 and TIMP-3 have potential therapeutic significance in maintaining intervertebral disc health and delaying degeneration.

The JNK signaling pathway in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) serves as the underlying pathology for various spinal degenerative conditions and is a primary contributor to low back pain (LBP). Recent studies have revealed a strong correlation between IDD and biological processes such as Programmed Cell Death (PCD), cellular senescence, inflammation, cell proliferation, extracellular matrix (ECM) degradation, and oxidative stress (OS). Of particular interest is the emerging evidence highlighting the significant involvement of the JNK signaling pathway in these fundamental biological processes of IDD. This paper explores the potential mechanisms through the JNK signaling pathway influences IDD in diverse ways. The objective of this article is to offer a fresh perspective and methodology for in-depth investigation into the pathogenesis of IDD by thoroughly examining the interplay between the JNK signaling pathway and IDD. Moreover, this paper summarizes the drugs and natural compounds that alleviate the progression of IDD by regulating the JNK signaling pathway. This paper aims to identify potential therapeutic targets and strategies for IDD treatment, providing valuable insights for clinical application.