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Mitophagy plays a crucial role in maintaining the homeostasis of intervertebral disc (IVD). Early Growth Response 1 (EGR1), a conservative transcription factor, is commonly upregulated under oxidative stress conditions and participates in regulating cellular senescence, apoptosis, and inflammatory responses. However, the specific role of EGR1 in nucleus pulposus (NP) cell senescence and mitophagy remains unclear. In this study, through bioinformatics analysis and validation using human tissue specimens, we found that EGR1 is significantly upregulated in IVD degeneration (IDD). Further experimental results demonstrate that knockdown of EGR1 inhibits TBHP-induced NP cell senescence and mitochondrial dysfunction while promoting the activation of mitophagy. The protective effect of EGR1 knockdown on NP cell senescence and mitochondrion disappears upon inhibition of mitophagy with mdivi1. Mechanistic studies reveal that EGR1 suppresses NP cell senescence and mitochondrial dysfunction by modulating the PINK1-Parkin dependent mitophagy pathway. Additionally, EGR1 knockdown delays acupuncture-induced IDD in rats. In conclusion, our study demonstrates that under TBHP-induced oxidative stress, EGR1 knockdown mitigates NP cell senescence and mitochondrial dysfunction through the PINK1-Parkin dependent mitophagy pathway, thereby alleviating IDD. [Display omitted] • Knocking down EGR1 inhibits TBHP-induced nucleus pulposus cell senescence. • Knocking down EGR1 promotes mitophagy. • Knocking down EGR1 inhibits nucleus pulposus cell senescence by activating PINK1-Parkin-regulated mitophagy. [ABSTRACT FROM AUTHOR]

The pathogenesis of intervertebral disc degeneration (IVDD) involves complex signaling networks and various effector molecules, and our understanding of the pathogenesis of IVDD is limited. Hypoxia inducible factor-1α (HIF-1α) is closely related to IVDD, and there is excessive oxidative stress concurrent with IVDD. In this study, we found that HIF-1α could protect nucleus pulposus cells from excessive oxidative stress by reversing the imbalance between oxidants and antioxidants and thus mitigating the oxidative stress-induced mitochondrial impairment. With further exploration, we found that pyruvate dehydrogenase kinase 1 (PDK-1) was involved in the protective effect of HIF-1α on nucleus pulposus cells under oxidative stress. We suggested that HIF-1α could preserve the mitochondrial integrity and activate glycolysis in nucleus pulposus cells via PDK-1, and the addition of DCA, a PDK-1 inhibitor, could blunt the protective effect of HIF-1α. In addition, the HIF-1α/PDK-1 regulatory axis was also confirmed in vivo through HIF-1α knockout mice model. Therefore, we propose that HIF-1α protects nucleus pulposus cells from excessive oxidative stress by maintaining the mitochondrial integrity and glycolysis via PDK-1, thus enriching the insight into the protective mechanism of HIF-1α against IVDD, and providing a novel therapeutic target for the treatment of IVDD. [Display omitted] • HIF-1α Maintains Redox Balance to Mitigate IVDD. • HIF-1α Preserves Mitochondrial Integrity Under Oxidative Stress. • HIF-1α Regulates Glycolysis via PDK-1 to Delay IVDD. [ABSTRACT FROM AUTHOR]

Discectomy is the surgical standard of care to relieve low back pain caused by intervertebral disc (IVD) herniation. However, there remains annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration, which often result in recurrent herniation (re-herniation). Herein, we develop a polyphenol-modified waterborne polyurethane bioadhesives (PPU-glues) to promote therapy prognosis after discectomy. Being composed of tannic acid (TA) mixed cationic waterborne polyurethane nanodispersions (TA/WPU+) and curcumin (Cur) embedded anionic waterborne polyurethane nanodispersions (Cur-WPU-), PPU-glue gels rapidly (<10 s) and exhibits low swelling ratios, tunable degradation rates and good biocompatibility. Due to the application of an adhesion strategy combing English ivy mechanism and particle packing theory, PPU-glue also shows considerable lap shear strength against wet porcine skin (≈58 kPa) and burst pressure (≈26 kPa). The mismatched particle sizes and the opposite charges of TA/WPU+ and Cur-WPU- in PPU-glue bring electrostatic interaction and enhance particle packing density. PPU-glue possesses superior reactive oxygen species (ROS)-scavenging capacity derived from polyphenols. PPU-glue can regulate extracellular matrix (ECM) metabolism in degenerated NP cells, and it can promote therapy biologically and mechanically in degenerated rat caudal discs. In summary, this study highlights the therapeutic approach that combines AF seal and NP augmentation, and PPU-glue holds great application potentials for post discectomy therapy. Currently, there is no established method for the therapy of annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration after discectomy. Herein, we developed a polyphenol-modified biomimetic polyurethane bioadhesive (PPU-glue) with strong adhesive strength and superior bioactive property. The adhesion strategy that combined a particle packing theory and an English ivy mechanism was firstly applied to the intervertebral disc repair field, which benefited AF seal. The modified method of incorporating polyphenols was utilized to confer with ROS-scavenging capacity, ECM metabolism regulation ability and anti-inflammatory property, which promoted NP augmentation. Thus, PPU-glue attained the synergy effect for post discectomy therapy, and the design principle could be universally expanded to the bioadhesives for other surgical uses. [Display omitted] [ABSTRACT FROM AUTHOR]

The stress relaxation of the TZ region, located at the interface of the Annulus Fibrosus (AF) and Nucleus Pulposus (NP) of the disc, and how its stress is relaxed compared to the adjacent regions is unknown. The current study aimed to identify the TZ stress relaxation properties under different strain magnitudes (0.2, 0.4, and 0.6 mm/mm) and compared the TZ stress relaxation characteristics to the NP and inner AF (IAF) regions at a specific strain magnitude (0.6 mm/mm). The results of the current study revealed that the TZ region exhibited different stress relaxation properties under various strain magnitudes with significantly higher initial (p < 0.008) and reduced stresses (marginally; p = 0.06) at higher strains. Our experimental stress relaxation data revealed a significantly higher equilibrium stress for the IAF compared to the TZ and NP regions (p < 0.001) but not between the TZ and NP regions (p = 0.7). We found that NP radial stress relaxed significantly faster (p < 0.04) than the TZ and NP. Additionally, the current study proposed a simple mathematical model and identified that, consistent with experimental data, the overall effect of region on both the level of decayed stress and the rate at which stress is relaxed was significant (p < 0.006). The current study found a similar stress relaxation characteristic between the NP and TZ regions, while IAF exhibited different stress relaxation properties. It is possible that this mismatch in stress relaxation acts as a shape transformation mechanism triggered by viscoelastic behavior. Our understanding of the biomechanical properties of the transition zone (TZ) in the IVD, a region at the interface of the Nucleus Pulposus (NP) and Annulus Fibrosus (AF), is sparse. Unfortunately, there are no current studies that investigate the TZ stress relaxation properties and how stress is relaxed in the TZ compared to the adjacent regions. For the first time, the current study characterized the stress relaxation properties of the TZ and described how the TZ stress is relaxed compared to its adjacent regions. [Display omitted] [ABSTRACT FROM AUTHOR]

Presently, the clinical treatment of intervertebral disc degeneration (IVDD) remains challenging, but the strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in the nucleus pulposus (NP) has become an effective way to alleviate IVDD. IL-1ra, a natural antagonist against IL-1β, can mitigate inflammation and promote regeneration in IVDD. Chondroitin sulfate (CS), an important component of the NP, can promote ECM synthesis and delay IVDD. Thus, these were chosen and integrated into functionalized microspheres to achieve their synergistic effects. First, CS-functionalized microspheres (GelMA-CS) with porous microstructure, good monodispersion, and about 200 µm diameter were efficiently and productively fabricated using microfluidic technology. After lyophilization, the microspheres with good local injection and tissue retention served as the loading platform for IL-1ra and achieved sustained release. In in vitro experiments, the IL-1ra-loaded microspheres exhibited good cytocompatibility and efficacy in inhibiting the inflammatory response of NP cells induced by lipopolysaccharide (LPS) and promoting the secretion of ECM. In in vivo experiments, the microspheres showed good histocompatibility, and local, minimally invasive injection of the IL-1ra-loaded microspheres could reduce inflammation, maintain the height of the intervertebral disc (IVD) and the water content of NP close to about 70 % in the sham group, and retain the integrated IVD structure. In summary, the GelMA-CS microspheres served as an effective loading platform for IL-1ra, eliminated inflammation through the controlled release of IL-1ra, and promoted ECM synthesis via CS to delay IVDD, thereby providing a promising intervention strategy for IVDD. The strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in nucleus pulposus (NP) has shown great potential prospects for alleviating intervertebral disc degeneration (IVDD). From the perspective of clinical translation, this study developed chondroitin sulfate functionalized microspheres to act as the effective delivery platform of IL-1ra, a natural antagonist of interleukin-1β. The IL-1ra loading microspheres (GelMA-CS-IL-1ra) showed good biocompatibility, good injection with tissue retention, and synergistic effects of inhibiting the inflammatory response induced by lipopolysaccharide and promoting the secretion of ECM in NPCs. In vivo , they also showed the beneficial effect of reducing the inflammatory response, maintaining the height of the intervertebral disc and the water content of the NP, and preserving the integrity of the intervertebral disc structure after only one injection. All demonstrated that the GelMA-CS-IL-1ra microspheres would have great promise for the minimally invasive treatment of IVDD. [Display omitted] [ABSTRACT FROM AUTHOR]

• Effects of osmotic and hydrostatic pressure (HP) and confinement on nucleus pulposus (NP) cells were investigated. • Confinement and constant HP counteract the swelling of NP cells and help retain sulfated glycosaminoglycan. • Aggrecan core protein gene is significantly upregulated under confinement and constant HP. • NPs' metabolic turnover is regulated by the configuration of actin and fibrillar extracellular matrices under HP. • These findings will assist understanding stress loading in the NP and replicate the native environment ex vivo for therapy. 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 h. 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. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) may profoundly impact the quality of life across the globe, and intervertebral disc degeneration (IVDD) is the major cause of LBP; however, targeted pharmaceutical interventions for IVDD are still lacking. Ferroptosis is a novel form of iron-dependent programmed cell death. Studies have showed that ferroptosis may closely associate with IVDD; thus, targeting ferroptosis may have great potential for IVDD therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line medications for LBP, while nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key inhibitory protein for ferroptosis. In the current study, we conducted a molecular docking screening between NSAIDs library and Nrf2 protein. Tinoridine was shown to have a high binding affinity to Nrf2. The in vitro study in nucleus pulposus (NP) cells showed that Tinoridine may promote the expression and activity of Nrf2, it may also rescue RSL3-induced ferroptosis in NP cells. Knockdown of Nrf2 reverses the protective effect of Tinoridine on RSL3-induced ferroptosis in NP cells, suggesting that the inhibitory effect of Tinoridine on ferroptosis is through Nrf2. In vivo study demonstrated that Tinoridine may attenuate the progression of IVDD in rats. As NSAIDs are already clinically used for LBP therapy, the current study supports Tinoridine's application from the view of ferroptosis inhibition. • Ferroptosis plays a critical role in intervertebral disc degeneration (IVDD), contributing significantly to its pathological progression. • Tinoridine, as an NSAID, can treat IVDD by inhibiting ferroptosis both in vitro and in vivo. • These findings highlight the therapeutic promise of Tinoridine in IVDD therapy. [ABSTRACT FROM AUTHOR]

Epigenetic changes are important considerations for degenerative diseases. DNA methylation regulates crucial genes by epigenetic mechanism, impacting cell function and fate. DNA presents hypermethylation in degenerated nucleus pulposus (NP) tissue, but its role in intervertebral disc degeneration (IVDD) remains elusive. This study aimed to demonstrate that methyltransferase mediated hypermethylation was responsible for IVDD by integrative bioinformatics and experimental verification. Methyltransferase DNMT3B was highly expressed in severely degenerated NP tissue (involving human and rats) and in-vitro degenerated human NP cells (NPCs). Bioinformatics elucidated that hypermethylated genes were enriched in oxidative stress and ferroptosis, and the ferroptosis suppressor gene SLC40A1 was identified with lower expression and higher methylation in severely degenerated human NP tissue. Cell culture using human NPCs showed that DNMT3B induced ferroptosis and oxidative stress in NPCs by downregulating SLC40A1, promoting a degenerative cell phenotype. An in-vivo rat IVDD model showed that DNA methyltransferase inhibitor 5-AZA alleviated puncture-induced IVDD. Taken together, DNA methyltransferase DNMT3B aggravates ferroptosis and oxidative stress in NPCs via regulating SLC40A1. Epigenetic mechanism within DNA methylation is a promising therapeutic biomarker for IVDD. [Display omitted] • DNMT3B is highly expressed in degenerated intervertebral disc tissue and plays an important role in NPCs degeneration. • DNMT3B enhanced degenerative cell phenotype by inducing NPCs ferroptosis. • SLC40A1 is a pivotal molecule within DNMT3B-mediated ferroptosis. [ABSTRACT FROM AUTHOR]

Nucleus pulposus cells survive in a hypoxic, acidic, nutrient-poor, and hypotonic microenvironment. Consequently, they maintain low proliferation and undergo autophagy to protect themselves from cellular stress. Therefore, we aimed to identify autophagy-related biomarkers involved in intervertebral disc degeneration pathogenesis. Autophagy-related differentially expressed genes were derived from the intersection between the public GSE147383 microarray data set to identify differentially expressed genes and online databases to identify autophagy-related genes. Furthermore, we assessed their biological functions with gene annotation and enrichment analysis in the Metscape portal. Then, the STRING database and Cytoscape software allowed inferring a protein-protein interaction (PPI) network and identifying hub genes. In addition, to predict transcription factors that may regulate the hub genes, we used the GeneMANIA website. Finally, the competing endogenous RNA prediction tools and Cytoscape were also used to construct an mRNA-miRNA-lncRNA network. A total of 123 autophagy-related differentially expressed genes were identified, they were mainly involved in phosphoinositide 3-kinase-Akt signaling, autophagy animal, and apoptosis pathways. Nine were identified as hub genes (PTEN, MYC, CTNNB1, JUN, BECN1, ERBB2, FOXO3, ATM, and FN1) and 36 transcription factors were associated with them. Finally, an autophagy-associated competing endogenous RNA network was constructed based on the 9 hub genes. Nine hub genes were identified and a network of competing endogenous RNA associated with autophagy was established. They can be used as autophagy-related biomarkers of intervertebral disc degeneration and for further exploration. [ABSTRACT FROM AUTHOR]

• Syndecan 4 null mice show vertebral osteopenia, reduced bone stiffness, and functionally altered bone biomechanics. • Osteopenic phenotype in Sdc4 null mice is driven by elevated osteoclast numbers. • Syndecan 4 fine-tunes collagen maturity and ECM composition in the intervertebral disc during early adult life. • Transcriptomic analysis shows dysregulation in heparan sulfate biosynthesis, UPR, and degradation along with decreased mitochondria metabolism. Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of Sdc4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that Sdc4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in Sdc4 KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. This was an experimental study. Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8–9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1β, and IL-6 mRNA levels in the injured (Co8–9) and adjacent discs (Co7–8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7–8 and Co8–9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7–8 and Co8–9 intervertebral discs showed roughly the same trend as mRNA levels. Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain. [ABSTRACT FROM AUTHOR]

There are many models of lumbar disc degeneration, but mechanical stress-induced lumbar disc degeneration is rare. Here we propose a mechanical stress-induced lumbar disc degeneration model to better understand the molecular mechanism of lumbar disc degeneration under stress stimulation. To design a new model of lumbar disc degeneration under mechanical stress. The anatomic approach of the oblique lateral approach to lumbar fusion surgery was used to design a longitudinal compression device across the vertebral body of the rabbit to impose longitudinal load on the lumbar disc. New Zealand white rabbits (n=30) were used. Screws were used to cross the rabbits' lumbar vertebral bodies, and both sides of the screws were pressurized. Continuous compression was then performed for 28 days. Adjacent unpressurized lumbar discs serve as controls for pressurized lumbar discs. At 28 days after surgery, micro-computed tomography (CT) and magnetic resonance imaging (MRI) were performed on the rabbits' lumbar discs. After the imaging examination, lumbar disc samples were removed, Safranin-O fast green and immunofluorescence was performed to detect the expression level of intervertebral disc degeneration-related proteins. The CT results showed that the disc height did not decrease significantly after mechanical loading. The MRI results showed that the signals in the pressurized disc decreased 28 days after loading. The results of Safranin-O fast green showed that the cartilage component of the intervertebral disc after mechanical compression was significantly reduced. The immunofluorescence results showed that the expression of ADAMTS5 and MMP13 protein in the nucleus pulposus of the intervertebral disc after mechanical compression increased, while the expression of SOX9 decreased, and the difference was statistically significant. Aggrecan's protein expression decreased, but was not statistically significant. This study designed a reliable model of disc degeneration in rabbits. It is more likely to mimic disc compression in the human body. This animal model can be used as a basic model to study the molecular physiological mechanisms of discogenic low back pain. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the clinical efficacy of percutaneous endoscopic suprapedicular decompression in treatment of down-migrated lumbar disc herniation. The clinical data of 43 patients with down-migrated lumbar disc herniation treated with endoscopic surgery at our hospital between January 2022 and January 2023 were retrospectively analyzed. Twenty-two and 21 patients underwent percutaneous endoscopic decompression using the suprapedicular and transforaminal endoscopic surgical system approaches, respectively. The perioperative, follow-up, and imaging data of the groups were compared. Surgery was uneventful in both groups. The number of intraoperative fluoroscopies and duration of surgery were significantly lower in the suprapedicular group (P < 0.05). The patients in both groups were followed up for at least 12 months. At the last follow-up, lumbar pain and leg pain visual analog scale, Oswestry Disability Index, and 36-Item Short Form Health Survey scores were significantly improved in both groups compared with preoperative values (P < 0.05); the differences in these indexes between the 2 groups were not significant preoperatively (P > 0.05). However, at the last postoperative follow-up, lumbar pain visual analog scale scores were significantly better in the suprapedicular group (0.83 ± 0.85 vs. 2.54 ± 1.32, P < 0.05). There was no significant change in intervertebral space height or lumbar lordotic angle compared with preoperative values in either group at the last follow-up (P > 0.05). However, the spinal canal cross-sectional area significantly increased (P < 0.05). The treatment of down-migrated lumbar disc herniation via a suprapedicular approach enabled the incision of the superior margin of the pedicle as needed under direct vision, involved less fluoroscopy while preserving facet joint stability, and enabled targeted removal of the herniated nucleus pulposus, thus greatly reducing residual nucleus pulposus. This surgical procedure was safe, rapid, and showed satisfactory therapeutic efficacy. [ABSTRACT FROM AUTHOR]

To investigate the influence of sacroiliac interosseous ligament tension and laxity on the biomechanics of the lumbar spine. A static analysis of a three-dimensional finite element model of the Lumbar-Pelvic is conducted to verify the model's effectiveness. Adjusting the sacroiliac ligament's elasticity modulus under a 10Nm lumbar flexion/extension moment, it simulates ligament tension/laxity to calculate vertebrae displacements, intervertebral disc stress and deformation, nucleus pulposus pressure, facet joint force, and ligament stress. With the elastic modulus of the sacroiliac ligament changing by +50%, −50%, and −90%, the angular displacement of vertebra 3 in forward flexion changes by +1.64%, −4.84%, and −42.3%, and the line displacements change by +5.7%, −16.4%, and −144.9%, respectively; and the angular displacements in backward extension change by +0.2%, −0.6%, −5.9% and the line displacements change by +5.5%, −14.3%, and −125.8%. However, the angular displacement and center distance between adjacent vertebrae do not change, leading to no change in the maximum stress of the intervertebral disc and the maximum pressure in the nucleus pulposus. Flexion and extension directly affect the deformation and stress magnitude and distribution in the lumbar spine. While sacroiliac interosseous ligament laxity and tension have little effect on disc deformation and stress, and nucleus pulposus pressure, they reduce the stability of the lumbar-sacral vertebrae. In a forward flexion state, the lumbar ligaments bear a large load and are prone to laxity, thereby increasing the risk of lumbar injury. [ABSTRACT FROM AUTHOR]

Low back pain is a leading cause of disability worldwide, often attributed to intervertebral disc (IVD) degeneration with loss of the functional nucleus pulposus (NP). Regenerative strategies utilizing biomaterials and stem cells are promising for NP repair. Human NP tissue is highly viscoelastic, relaxing stress rapidly under deformation. However, the impact of tissue-specific viscoelasticity on the activities of adipose-derived stem cells (ASC) remains largely unexplored. Here, we investigated the role of matrix viscoelasticity in regulating ASC differentiation for IVD regeneration. Viscoelastic alginate hydrogels with stress relaxation time scales ranging from 100 s to 1000s were developed and used to culture human ASCs for 21 days. Our results demonstrated that the fast-relaxing hydrogel significantly enhanced ASCs long-term cell survival and NP-like extracellular matrix secretion of aggrecan and type-II collagen. Moreover, gene expression analysis revealed a substantial upregulation of the mechanosensitive ion channel marker TRPV4 and NP-specific markers such as SOX9, HIF-1α, KRT18, CDH2 and CD24 in ASCs cultured within the fast-relaxing hydrogel, compared to slower-relaxing hydrogels. These findings highlight the critical role of matrix viscoelasticity in regulating ASC behavior and suggest that viscoelasticity is a key parameter for novel biomaterials design to improve the efficacy of stem cell therapy for IVD regeneration. Systematically characterized the influence of tissue-mimetic viscoelasticity on ASC. NP-mimetic hydrogels with tunable viscoelasticity and tissue-matched stiffness. Long-term survival and metabolic activity of ASCs are substantially improved in the fast-relaxing hydrogel. The fast-relaxing hydrogel allows higher rate of cell protrusions formation and matrix remodeling. ASC differentiation towards an NP-like cell phenotype is promoted in the fast-relaxing hydrogel, with more CD24 positive expression indicating NP committed cell fate. The expression of TRPV4 , a molecular sensor of matrix viscoelasticity, is significantly enhanced in the fast-relaxing hydrogel, indicating ASC sensing matrix viscoelasticity during cell development. The NP-specific ECM secretion of ASC is considerably influenced by matrix viscoelasticity, where the deposition of aggrecan and type-II collagen are significantly enhanced in the fast-relaxing hydrogel. [Display omitted] [ABSTRACT FROM AUTHOR]

Lumbar disc herniation (LDH) results in low back pain due to nerve root compression caused by nucleus pulposus degeneration. Chemonucleolysis of the nucleus pulposus by injection of condoliase is less invasive than surgery, but may cause disc degeneration. The purpose of the study was to examine outcomes of condoliase injection in patients in their teens and twenties using Pfirrmann criteria on MRI. A single-center retrospective study was performed in 26 consecutive patients (19 men, 7 women) who underwent condoliase injection (1 mL, 1.25 U/mL) for LDH and had MRI scans at 3 and 6 months. Cases with and without an increase in Pfirrmann grade at 3 months post-injection were included in groups D (disc degeneration, n = 16) and N (no degeneration, n = 10). Pain was measured on a visual analogue scale (VAS). MRI findings were evaluated using the % change in disc height index (ΔDHI). The mean age of the patients was 21.1 ± 4.1 years and 12 were <20 years old. At baseline, 4, 21 and 1 were in Pfirrmann grades II, III and IV. In group D, no case had a further increase in Pfirrmann grade from 3 to 6 months. Pain significantly decreased in both groups. There were no adverse events. MRI showed a significant decrease in ΔDHI from 100% pre-injection to 89.4 ± 9.7% at 3 months in all cases (p < 0.05). There was a significant recovery in ΔDHI in group D from 3 to 6 months (85.4 ± 9.3% vs. 86.7 ± 9.1%, p < 0.05). These results suggest that chemonucleolysis with condoliase is effective and safe for LDH in young patients. Progression of Pfirrmann criteria at 3 months post-injection occurred in 61.5% of cases, but disc degeneration showed recovery in these patients. A longer-term study of the clinical symptoms related to these changes is required. [ABSTRACT FROM AUTHOR]

Low back pain resulting from disc degeneration is a leading cause of disability worldwide. However, to date few therapies target the cause and fail to repair the intervertebral disc (IVD). This study investigates the ability of an injectable hydrogel (NPgel), to inhibit catabolic protein expression and promote matrix expression in human nucleus pulposus (NP) cells within a tissue explant culture model isolated from degenerate discs. Furthermore, the injection capacity of NPgel into naturally degenerate whole human discs, effects on mechanical function, and resistance to extrusion during loading were investigated. Finally, the induction of potential regenerative effects in a physiologically loaded human organ culture system was investigated following injection of NPgel with or without bone marrow progenitor cells. Injection of NPgel into naturally degenerate human IVDs increased disc height and Young's modulus, and was retained during extrusion testing. Injection into cadaveric discs followed by culture under physiological loading increased MRI signal intensity, restored natural biomechanical properties and showed evidence of increased anabolism and decreased catabolism with tissue integration observed. These results provide essential proof of concept data supporting the use of NPgel as an injectable therapy for disc regeneration. Low back pain resulting from disc degeneration is a leading cause of disability worldwide. However, to date few therapies target the cause and fail to repair the intervertebral disc. This study investigated the potential regenerative properties of an injectable hydrogel system (NPgel) within human tissue samples. To mimic the human in vivo conditions and the unique IVD niche, a dynamically loaded intact human disc culture system was utilised. NPgel improved the biomechanical properties, increased MRI intensity and decreased degree of degeneration. Furthermore, NPgel induced matrix production and decreased catabolic factors by the native cells of the disc. This manuscript provides evidence for the potential use of NPgel as a regenerative biomaterial for intervertebral disc degeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation. [Display omitted] • Mitochondria-associated endoplasmic reticulum membrane (MAM) structure defect contributes to the pathogenesis of IDD. • MAM structure participates in regulating mitochondrial dynamics and Zn2+ homeostasis. • SYNJ2BP is identified as one critical regulator of MAM structure in human NP cells. • Restoring SYNJ2BP function shows a great potential for alleviating NP cell senescence and rejuvenating intervertebral disc. [ABSTRACT FROM AUTHOR]

Etiology of adolescent idiopathic scoliosis (AIS) is still unknown. Prior in vitro research suggests intervertebral disc pathomorphology as a cause for the initiation and progression of the spinal deformity, however, this has not been well characterized in vivo. To quantify and compare lumbar disc health and morphology in AIS to controls. Cross-sectional study. All lumbar discs were imaged using a 3T MRI scanner. T2-weighted and quantitative T2* maps were acquired. Axial slices of each disc were reconstructed, and customized scripts were used to extract outcome measurements: Nucleus pulposus (NP) signal intensity and location, disc signal volume, transition zone slope, and asymmetry index. Pearson's correlation analysis was performed between the NP location and disc wedge angle for AIS patients. ANOVAs were utilized to elucidate differences in disc health and morphology metrics between AIS patients and healthy controls. α=0.05. There were no significant differences in disc health metrics between controls and scoliotic discs. There was a significant shift in the NP location towards the convex side of the disc in AIS patients compared to healthy controls, with an associated increase of the transition zone slope on the convex side. Additionally, with increasing disc wedge angle, the NP center migrated towards the convex side of the disc. The present study elucidates morphological distinctions of intervertebral discs between healthy adolescents and those diagnosed with AIS. Discs in patients diagnosed with AIS are asymmetric, with the NP shifted towards the convex side, which was exacerbated by an increased disc wedge angle. Investigation of the MRI signal distribution (T2w and T2* maps) within the disc suggests an asymmetric pressure gradient shifting the NP laterally towards the convexity. Quantifying the progression of these morphological alterations during maturation and in response to treatment will provide further insight into the mechanisms of curve progression and correction, respectively. [ABSTRACT FROM AUTHOR]

The progression of intervertebral disc degeneration (IDD) is attributed to the gradual exacerbation of cellular apoptosis and impaired extracellular matrix (ECM) synthesis, both of which are induced by progressive inflammation. Therefore, it is crucial to address the inflammatory microenvironment and rectify the excessive apoptosis of nucleus pulposus cells (NPCs) to achieve intervertebral disc (IVD) regeneration. In this study, we devised a smart microgel gene delivery system that incorporates functionalized gene nanoparticles (NPs) for the purpose of IVD regeneration. siGrem1 was loaded into the NPs to enhance their antiapoptotic ability and protective effects. Furthermore, the encapsulation of HADA further endows the NPs (referred to as HSGN) with targeted delivery and anti-inflammatory effects, as well as reactive oxygen species (ROS) scavenging capacities. To create an microenvironment-responsive microgel system, phenylboronic acid-functionalized microspheres (referred to as M.S.) were fabricated and dynamically loaded with the HSGN. This microgel system (MHSGN), which is highly biocompatible, enables the sustained release of siGrem1, effectively modulating inflammation, scavenging ROS, and alleviating apoptosis in NPCs. These multifunctional capabilities promote the restoration of metabolic homeostasis within the nucleus pulposus ECM, ultimately leading to delayed IDD. [Display omitted] • A gene nanoparticle with targeted gene delivery capability is fabricated. • Anti-inflammation and reactive oxygen species scavenging capabilities is incoperated. • Apoptosis is regulated in degenerated intervertebral disc. • A funcionalized smart microgel is constructed. • Gene nanoparticle is responsively released. [ABSTRACT FROM AUTHOR]

A herniated intervertebral disc (IVD) is a common injury in the human population. Despite the injury being isolated to a singular IVD in the spine, it is important to look at the biomechanical effects that a damaged IVD has on the entire spine, specifically the IVD adjacent to the injury. This study examined the effects of a damaged IVD on the mechanical properties of the annulus fibrosus (AF) in the adjacent cranial IVD. Basic science study using an in-vitro porcine model. Sixteen porcine cervical spines were used; specifically spinal levels C3/4/5 were assigned to one of two experimental groups: 1) a control group that was not subjected any injuries (n=8); 2) an experimental group that experienced an injury to the anterolateral part of the disc, reaching the nucleus pulposus but without affecting the posterior portion of the AF in the C4/5 functional spine unit (FSU) (n=8). Each specimen underwent a previously published precondition compression protocol of 300 N of compression for 15 minutes followed by a cyclical compression protocol of compression protocol of 0.5 Hz sinusoidal waveform at 300 to 1200 N for 2 hours (3600 cycles). Post compression, the C3/4 AF was dissected to obtain two multilayer samples (one anterior and one posterior) as well as a peel sample (from the posterolateral region). A tensile strength test was conducted to examine the strength of the interlamellar matrix (peel sample) and the overall strength of the AF (multilayer samples). Significant results were found in the peel test samples. Specifically, experimental specimens were less stiff compared than control specimens (p<.01). In addition, experimental specimens also had a lower average strength then control specimens (p <.01). This reduction in both interlamellar strength and stiffness increases the risk of delamination in the experimental samples. In contrast, there were no differences found between the two groups when examining the AF as a whole through the multilayer tests (p>.05). It appears that a damaged IVD impacts the biomechanics of the spine and specifically the mechanical properties of the adjacent IVD. Specifically, the observed weakening of the interlamellar matrix in these adjacent IVDs may predispose it to delamination and subsequently degeneration or herniation. These findings may help clinicians when treating patients who have experienced a disc herniation or severe degeneration, as they may potentially experience accelerated adjacent disc degeneration. [ABSTRACT FROM AUTHOR]

We explored the biomechanical changes of 2 conventional minimally invasive nonfusion surgical methods for treating disc herniation in adjacent segment disease using 3-dimensional finite element analysis. A model comprising L3 to the sacrum was validated and used to establish an L4-L5 fusion model, and an adjacent segment disease (ASD) model was developed by modifying the material properties of the intervertebral discs. The ASD model was used to simulate 2 conventional minimally invasive nonfusion surgical methods, which resulted in the creation of 2 postoperative models (M1 and M2). The range of motion and the equivalent stress for each model were recorded under 6 different working conditions. The data are descriptive and were analyzed comparatively under a normal load. Compared with the ASD group, the range of motion of the adjacent segment in the M1 and M2 groups remained unaffected. However, significant Von-Mises stress changes were found in the annulus fibrosus and nucleus pulposus (NP), especially during extension, ipsilateral bending, and rotation. Stress in the NP also shifted toward the surgical incision in the annulus fibrosus during these movements. The maximum Von-Mises stress in the NP of the cephalic segment increased more than did that of the caudal segment. Minimal nonfusion surgery for ASD might not affect adjacent segment stability significantly. Nonetheless, it can lead to segmental degeneration deterioration and postoperative recurrence. The cephalic segment is affected more than the caudal segment. Therefore, consideration of disc degeneration and appropriate selection of surgical methods for ASD are crucial. [ABSTRACT FROM AUTHOR]

Degenerative intervertebral disc disease is a common source of chronic pain and reduced quality of life in people over the age of 40. While degeneration occurs throughout the disc, it most often initiates in the nucleus pulposus (NP). Minimally invasive delivery of NP cells within hydrogels that can restore and maintain the disc height while regenerating the damaged NP tissue is a promising treatment strategy for this condition. Towards this goal, a biohybrid ABA dimethacrylate triblock copolymer was synthesized, possessing a lower critical solution temperature below 37 °C and which contained as its central block an MMP-degradable peptide flanked by poly(trimethylene carbonate) blocks bearing pendant oligoethylene glycol groups. This triblock prepolymer was used to form macroporous NP cell-laden hydrogels via redox initiated (ammonium persulfate/sodium bisulfite) crosslinking, with or without the inclusion of thiolated chondroitin sulfate. The resulting macroporous hydrogels had water and mechanical properties similar to those of human NP tissue and were mechanically resilient. The hydrogels supported NP cell attachment and growth over 28 days in hypoxic culture. In hydrogels prepared with the triblock copolymer but without the chondroitin sulfate the NP cells were distributed homogeneously throughout in clusters and deposited collagen type II and sulfated glycosaminoglycans but not collagen type I. This hydrogel formulation warrants further investigation as a cell delivery vehicle to regenerate degenerated NP tissue. The intervertebral disc between the vertebral bones of the spine consists of three regions: a gel-like central nucleus pulposus (NP) within the annulus fibrosis, and bony endplates. Degeneration of the intervertebral disc is a source of chronic pain in the elderly and most commonly initiates in the NP. Replacement of degenerated NP tissue with a NP cell-laden hydrogel is a promising treatment strategy. Herein we demonstrate that a crosslinkable polymer with a lower critical solution temperature below 37 °C can be used to form macroporous hydrogels for this purpose. The hydrogels are capable of supporting NP cells, which deposit collagen II and sulfated glycosaminoglycans, while also possessing mechanical properties matching those of human NP tissue. [Display omitted] [ABSTRACT FROM AUTHOR]

The strategies for modulating the local inflammatory microenvironment to inhibit intervertebral disc degeneration (IVDD) have garnered significant interest in recent years. In this study, we developed a "self-contained" injectable hydrogel capable of storing Mg2+ while carrying nucleus pulposus (NP) cells, with the aim of inhibiting IVDD through immunoregulation. The hydrogel consists of sodium alginate (SA), poly(N-isopropylacrylamide) (PNIPAAm), silicate ceramics (SC), and NP cells. When injected into the NP site, PNIPAAm gelates instantly under body temperature, forming an interpenetrating network (IPN) hydrogel with SA. Ca2+ released from the SC can crosslink the SA in situ , forming a SA/PNIPAAm hydrogel with an interpenetrating network (IPN) encapsulating the NP cells. Moreover, inside the hydrogel, Mg2+ released from SC are effectively encapsulated and maintained at a desirable concentration. These Mg2+ facilitates the local cell matrix synthesis and promotes immunomodulation (upregulating M2 / downregulating M1 macrophage polarization), thus inhibiting the IVDD progression. The proposed hydrogel has biocompatibility and is shown to enhance the expression of collagen II (COL II) and aggrecan. The potential of the injectable hydrogel in IVD repair has also been successfully demonstrated by in vivo studies. • A unique injectable hydrogel consisting of sodium alginate (SA), poly(N-isopropylacrylamide) (PNIPAAm), silicate ceramics (SC) and nucleus pulposus cells, has been created for intervertebral disc repair applications. • This is the first "self-contained" cell delivery system capable of releasing and subsequently storing Mg2+ in the hydrogel reservoir for localized treatment. • The role of Mg2+ in regulating the macrophage polarity transformation (from pro-inflammatory M1 to anti-inflammatory M2 phenotype) has been unveiled in the context of intervertebral disc repair. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) is an incurable, specific treatment-orphan disease with an increasing burden worldwide. Although great efforts have been made to develop new regenerative therapies, their clinical success is limited. Characterize the metabolomic and gene expression changes underpinning human disc degeneration. This study also aimed to disclose new molecular targets for developing and optimizing novel biological approaches for IVDD. Intervertebral disc cells were obtained from IVDD patients undergoing circumferential arthrodesis surgery or from healthy subjects. Mimicking the harmful microenvironment of degenerated discs, cells isolated from the nucleus pulposus (NP) and annulus fibrosus (AF) were exposed to the proinflammatory cytokine IL-1β and the adipokine leptin. The metabolomic signature and molecular profile of human disc cells were unraveled for the first time. The metabolomic and lipidomic profiles of IVDD and healthy disc cells were analyzed by high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Gene expression was investigated by SYBR green-based quantitative real-time RT-PCR. Altered metabolites and gene expression were documented. Lipidomic analysis revealed decreased levels of triacylglycerols (TG), diacylglycerol (DG), fatty acids (FA), phosphatidylcholine (PC), lysophosphatidylinositols (LPI) and sphingomyelin (SM), and increased levels of bile acids (BA) and ceramides, likely promoting disc cell metabolism changing from glycolysis to fatty acid oxidation and following cell death. The gene expression profile of disc cells suggests LCN2 and LEAP2/GHRL as promising molecular therapeutic targets for disc degeneration and demonstrates the expression of genes related to inflammation (NOS2, COX2, IL-6, IL-8, IL-1β , and TNF-α) or encoding adipokines (PGRN, NAMPT, NUCB2, SERPINE2 , and RARRES2), matrix metalloproteinases (MMP9 and MMP13), and vascular adhesion molecules (VCAM1). Altogether, the presented results disclose the NP and AF cell biology changes from healthy to degenerated discs, allowing the identification of promising molecular therapeutic targets for intervertebral disc degeneration. Our results are relevant to improving current biological-based strategies aiming to repair IVD by restoring cellular lipid metabolites as well as adipokines homeostasis. Ultimately, our results will be valuable for successful, long-lasting relief of painful IVDD. [ABSTRACT FROM AUTHOR]

Lumbar disc herniation (LDH) is a common cause of low back pain and is associated with degeneration of the nucleus pulposus causing nerve root compression. Chemonucleolysis of the nucleus pulposus with condoliase is a low-invasive treatment for LDH. The purpose of this study was to investigate changes in Pfirrmann criteria, which are used to evaluate disc degeneration, after injection of condoliase into a herniated intervertebral disc, and to identify factors associated with disc degeneration at 3 months post-injection. Medical records and radiographic findings were reviewed retrospectively for 127 patients with LDH (88 male, 39 female, mean age: 46.6 ± 17.1 years, mean follow-up: 9.8 ± 7.8 months) who underwent chemonucleolysis with intradiscal condoliase injection at our center since September 2018. Condoliase (1.25 U/mL; 1 mL volume) was injected toward the middle of the affected intervertebral nucleus pulposus using a 21-gauge disc-puncture needle. Cases in which the Pfirrmann grade did and did not progress in the 3 months after the injection were included in groups P (progression, n = 49) and NP (non-progression, n = 78), respectively. Logistic regression analysis of progression of Pfirrmann grade post-injection showed significant associations with age <40 years (p = 0.013, odds ratio (OR): 3.69, 95% confidence interval (CI): 1.32–10.31), Pfirrmann Grade II or III at baseline (p = 0.021, OR: 3.51, 95% CI: 1.24–9.64), and a high-intensity MRI signal in the herniation (p = 0.047, OR: 2.97, 95% CI: 1.03–8.87). Patients in group P had significantly higher rates of disc height decrease ≥20%, reduced herniated disc size, and improved VAS for pain, but both groups had significant decreases in pain. No cases had anaphylactic shock or neurologic sequelae. These results show the safety and efficacy of chemonucleolysis with condoliase for treatment of painful LDH. Progression of Pfirrmann criteria on MRI at 3 months after injection was significantly associated with an improved clinical outcome. [ABSTRACT FROM AUTHOR]

Global aging is leading to an increased incidence of geriatric diseases, namely degenerative scoliosis. Vesicular trafficking of proangiogenic factors drives the progression of intervertebral disc degeneration. Neovascularization promotes the infiltration of inflammatory cells in the nucleus pulposus. Matrix metalloproteinases contribute to the asymmetric remodeling of the extracellular matrix in the intervertebral disc. Osteoporosis and sarcopenia increase the risk of spine deformity, which predisposes patients to adult degenerative scoliosis. The global aging population has led to an increase in geriatric diseases, including adult degenerative scoliosis (ADS). ADS is a spinal deformity affecting adults, particularly females. It is characterized by asymmetric intervertebral disc and facet joint degeneration, leading to spinal imbalance that can result in severe pain and neurological deficits, thus significantly reducing the quality of life. Despite improved management, molecular mechanisms driving ADS remain unclear. Current literature primarily comprises epidemiological and clinical studies. Here, we investigate the molecular mechanisms underlying ADS, with a focus on angiogenesis, inflammation, extracellular matrix remodeling, osteoporosis, sarcopenia, and biomechanical stress. We discuss current limitations and challenges in the field and highlight potential translational applications that may arise with a better understanding of these mechanisms. [ABSTRACT FROM AUTHOR]

Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. IVD herniation manifests as the nucleus pulposus (NP) protruding beyond the boundaries of the intervertebral disc due to disruption of the annulus fibrosus (AF). With a deepening understanding of the importance of the AF structure in the pathogenesis of intervertebral disc degeneration, numerous advanced therapeutic strategies for AF based on tissue engineering, cellular regeneration, and gene therapy have emerged. However, there is still no consensus concerning the optimal approach for AF regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. However, there is still no consensus concerning the optimal approach for annulus fibrosus (AF) regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. [Display omitted] [ABSTRACT FROM AUTHOR]

A plethora of studies has substantiated the remarkable clinical efficacy of anterior cervical discectomy and fusion (ACDF) in the treatment of cervical spondylotic myelopathy. 1,2 This procedure effectively removes the posterior osteophytes and protruding nucleus pulposus, achieving direct decompression of the spinal cord and effectively alleviating compression symptoms. Concurrently, by distracting the intervertebral space, ACDF contributes to the restoration of the physiological curvature of the cervical spine. However, several pressing issues remain to be addressed during the surgical process. The depth of the surgical field and the lighting conditions often limit the clear identification of the spinal cord and surrounding delicate structures, compounded by the limited operating space and potential interference between the primary surgeon and assistants, all of which may increase surgical risks. 3,4 To surmount these challenges, the application of three-dimensional (3D) microscopy in anterior cervical surgery has been proven to be an effective solution. In Video 1, we demonstrate the complete 2-stage ACDF operation under 3D microscopy, where both the primary surgeon and the assistant observe the surgical area through monitors and external screens, ensuring a comfortable posture and good coordination. In our retrospective review, we analyzed 16 ACDF cases aided by 3D microscopy(including both cervical spondylotic myelopathy with disc herniation and cases with spinal instability). Based on the results of the normality test, we use mean (SD) to describe the data. The mean (SD) decompression time was 37.06 (13.30) minutes, with overall surgical duration of 114.56 (18.11) minutes and blood loss of 68.13 (21.36) mL, with no surgically related complications. At the 6-month follow-up, there was a significant improvement in the Japanese Orthopaedic Association score, neck disability index score, visual analog scale score, and C2-7 Cobb angle compared with preoperative values (Japanese Orthopaedic Association from 11.06 [1.00] to 15.38 [1.09], neck disability index from 30.75 [3.49] to 14.81 [2.93], visual analog scale from 5.19 [1.60] to 1.88 [0.96], and C2-7 Cobb angle from 11.97 [4.63] to 15.49 [4.06], respectively; P < 0.05). 3D microscopy–assisted ACDF demonstrated clear advantages in terms of decompression operation time, intraoperative blood loss, exposure and resection of the posterior longitudinal ligament, and complication rate, achieving satisfactory short-term therapeutic outcomes in the treatment of cervical spondylotic myelopathy. Assisted by 3D microscopy, ACDF surgery offers a high-definition visual field that enhances precision, thereby reducing procedural risks and improving clinical outcomes. This technology alleviates the physical strain on surgeons, fosters collaborative teamwork, and facilitates educational exchanges. With a relatively short learning curve, 3D microscopy significantly enhances the safety and efficiency of ACDF procedures. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration (IDD) and the consequent low back pain present a major medical challenge. Stem cell-based tissue engineering is promising for the treatment of IDD. However, stem cell-based treatment is severely impaired by the increased generation of reactive oxygen species (ROS) in degenerative disc, which can lead to a high level of cell dysfunction and even death. In this study, a kartogenin (KGN)@PLGA-GelMA/PRP composite hydrogel was designed and used as a carrier of ADSCs-based therapies in disc repair. Injectable composite hydrogel act as a carrier for controlled release of KGN and deliver ADSCs to the degenerative disc. The released KGN can stimulate the differentiation of ADSCs into a nucleus pulposus (NP) -like phenotype and boost antioxidant capacity of ADSCs via activating Nrf2/TXNIP/NLRP3 axis. Furthermore, the composite hydrogel combined with ADSCs attenuated the in vivo degeneration of rat IVDs, maintained IVD tissue integrity and accelerated the synthesis of NP-like extracellular matrix. Therefore, the KGN@PLGA-GelMA/PRP composite hydrogel is a promising strategy for stem cell-based therapies of IDD. [Display omitted] • KGN@PLGA-GelMA/PRP composite hydrogel combined with ADSCs attenuated the in vivo degeneration of rat IVDs. • KGN can stimulate the differentiation of ADSCs and boost antioxidant capacity of ADSCs via activating Nrf2/TXNIP/NLRP3 axis. • We chose to perform cell therapy one weeks after puncture, which is more realistic in terms of clinical practice. [ABSTRACT FROM AUTHOR]

Current studies suggest that the pathogenesis of intervertebral disc degeneration (IDD) is related to oxidative stress damage in nucleus pulposus cells (NPCs). N-acetylserotonin (NAS) is an effective scavenger of reactive oxygen species, but its role in IDD and its underlying mechanisms are not yet clear. Therefore, the aim of this study was to investigate the effect of NAS on oxidative stress injury in NPCs and its mechanism. NP tissue of rat intervertebral disc was collected and NPCs were isolated. NPCs were treated with H 2 O 2 to simulate the state of oxidative stress. The effects of NAS on cell viability, apoptosis, senescence, extracellular matrix (ECM), redox status and PI3K/AKT signal pathway were evaluated by cell counting kit-8, western blot, immunofluorescence, flow cytometry and SA-β-gal staining. Finally, the changes of the above indexes were further observed after the inhibition of PI3K pathway by LY294002. Flow cytometry showed that NAS reduced H 2 O 2 -induced apoptosis of NPCs. SA-β-Gal staining showed that H 2 O 2 -induced senescence of NP cells was reversed by NAS. Immunofluorescence staining showed that NAS inhibited H 2 O 2 -induced ECM degradation. Western blotting analysis revealed that NAS significantly decreased apoptosis, senescence and ECM degradation. Further analysis showed that NAS treatment activated the PI3K/AKT pathway in H 2 O 2 -stimulated NPCs. However, these protected effects were inhibited after LY294002 treatment. The results of the present study suggest that NAS inhibits H 2 O 2 -induced NPCs degeneration by activating PI3K/AKT pathway, suggesting that NAS has the potential to treat IDD. [ABSTRACT FROM AUTHOR]

Disk degeneration (DD) stands for the most common cause of low back pain. The establishment of an animal model plays an intrinsic role in the clarification of the physiopathology of DD. The purpose of this study is to select an optimal dose of monosodium iodoacetate (MIA) that may generate a reliable model of DD. Thirty-four rats were used in this study. The disks (Co7/8, Co8/9, and Co 9/10) received 1 shot of intradiskal injection of 0.02 mg, 0.1 mg, and 0.5 mg of MIA solution, respectively. Half of the rats were euthanized 3 weeks after MIA injection, and the other half 6 weeks after injection. Magnetic resonance imaging evaluation showed that the mean T2-weighted signal intensity at 6 weeks decreased significantly in the 0.1 and 0.5 mg groups. The disk height of the control group was significantly higher than those of the 0.1 mg and 0.5 mg groups. Histologic and macroscopic results revealed time-and-dose-depending degeneration in the disks that received MIA. Additionally, MIA produced cell death in the nucleus pulposus cells with an elevated percentage. The injected disk with 0.1 mg MIA demonstrated a progressive degeneration, the disk injected with 0.5 mg MIA induced DD acutely 3 weeks post MIA injection, while the dose of 0.02 mg of MIA did not show much degeneration. We concluded that 0.1 mg MIA is the most suitable dose to establish a model of DD, which enabled us to replicate the onset, progression, and outcome of diverse histopathologies of DD in the clinic. [ABSTRACT FROM AUTHOR]

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF- κ B) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD. Nim targeting SIRT1 protects NPCs by promoting cholesterol efflux and inhibiting inflammatory pathways and modulates macrophage polarization to create an immune microenvironment conducive to matrix synthesis of NPCs. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration is a very common disease worldwide and the leading cause of low back pain. Long noncoding RNAs are novel players in intervertebral disc degeneration and have multiple functions. This study explored the role of long noncoding RNA HCG18 in regulating extracellular matrix (ECM) degradation in nucleus pulposus cells (NPCs) during intervertebral disc degeneration. NPCs were subjected to interleukin-1β to induce a degenerative model of NPCs. Cell viability was assessed using Cell Counting Kit-8 assay. Messenger RNA and protein expressions were examined by real-time quantitative polymerase chain reaction and Western blot. The location of HCG18 was determined by nucleocytoplasmic separation assay. The binding relationships between HCG18 , MIR4306, and EPAS1 were verified by dual luciferase reporter gene assay and/or RNA immunoprecipitation assay. HCG18 was highly expressed in interleukin-1β–induced degenerated NPCs, which was associated with reduced collagen II and aggrecan expression and increased MMP-13 and ADAMTS-4 expression. HCG18 knockdown could remarkably inhibit ECM degradation in IL-1β–induced degenerated NPCs, while HCG18 overexpression had the opposite effect. Our molecular study further revealed that HCG18 could sponge MIR4306 , and HCG18 knockdown could suppress ECM degradation in degenerated NPCs by elevating MIR4306 expression. In addition, EPAS1 was identified as the direct target of MIR4306. As expected, MIR4306 overexpression inhibited ECM degradation in degenerated NPCs by downregulating EPAS1. HCG18 promoted ECM degradation in degenerated NPCs via regulation of the MIR4306 / EPAS1 axis. [ABSTRACT FROM AUTHOR]

Understanding the structure-function relationship in the intervertebral disk (IVD) is crucial for the development of novel tissue engineering strategies to regenerate IVD and the establishment of accurate computational models for low back pain research. A large number of studies have improved our knowledge of the mechanical and structural properties of the nucleus pulposus (NP) and annulus fibrosus (AF), two of the main regions in the IVD. However, few studies have focused on the AF-NP interface (transition zone; TZ). Therefore, the current study aims to, for the first time, characterize the cyclic and failure mechanical properties of the TZ region under physiological loading (1, 3, and 5% s −1 strain rates) and investigate the structural integration mechanisms between the NP, TZ, and AF regions. The results of the current study reveal significant effects of region (NP, TZ, and AF) and strain rates (1, 3, and 5% s −1) on stiffness (p < 0.001). In addition, energy absorption is significantly higher for the AF compared to the TZ and NP (p <0.001) as well as between the TZ and NP (p <0.001). The current research finds adaptation, direct penetration, and entanglement between TZ and AF fibers as three common mechanisms for structural integration between the TZ and AF regions. Despite a large number of studies that have mechanically, structurally, and biologically characterized the nucleus pulposus (NP) and annulus fibrosus (AF) regions, few studies have focused on the NP-AF interface region (known as Transition Zone; TZ) in the IVD; hence, our understanding of the TZ structure-function relationship is still incomplete. Of particular importance, the cyclic mechanical properties of the TZ, compared to the adjacent regions (NP and AF), are yet to be explored and the precise nature of the structural integration between the NP and AF via the TZ region is not yet known. The current study explores both the mechanical and structural properties of the TZ region to ultimately identify the mechanism of integration between the NP and AF. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) is a degenerative disease characterized by lower-back pain, causing disability globally. Antioxidant therapy is currently considered one of the most promising strategies for IVDD treatment, given the crucial role of reactive oxygen species (ROS) in IVDD pathogenesis. Herein, a ROS-responsive magnesium-containing microsphere (Mg@PLPE MS) was constructed for the antioxidative treatment of IVDD. The Mg@PLPE MS has a core-shell structure comprising poly(lactic- co -glycolic acid) (PLGA) and ROS-responsive polymer poly(PBT- co -EGDM) as the shell and a magnesium microparticle as the core. The poly(PBT- co -EGDM) can be destroyed by H 2 O 2 through the H 2 O 2 -triggered hydrophobic-to-hydrophilic transition, subsequently promoting an Mg-water reaction to produce H 2. Thus, Mg@PLPE MS provides a valuable platform for H 2 O 2 elimination and controlled H 2 release. The generated H 2 scavenge for ROS by reacting with noxious •OH. Notably, the Mg@PLPE MS exerted significant antioxidative and anti-inflammatory effects in a disc degeneration rat model and alleviated extracellular matrix degradation and disc cells apoptosis, thereby underlining its efficacy in IVDD treatment. The Mg@PLPE MS also exhibited robust biocompatibility and negligible toxicity, presenting the promise for the antioxidative treatment of IVDD in vivo. Antioxidant therapy is currently considered one of the most promising strategies for intervertebral disc degeneration (IVDD) treatment, given the crucial role of reactive oxygen species (ROS) in IVDD pathogenesis. Here, ROS-responsive magnesium-containing microspheres (Mg@PLPE MSs) were constructed to alleviate IVDD through controlled release of hydrogen gas. The Mg@PLPE MSs can effectively scavenge overproduced ROS by simultaneously reacting with H 2 O 2 and •OH, thus creating a suitable microenvironment for inhibition of ECM degradation. As a result, Mg@PLPE MSs treated IVDD rats exhibit minimal nucleus pulposus decrease, less extracellular matrix degradation, minimal radial fissure of fibrous rings, and higher disc height index. Therefore, the as-prepared Mg@PLPE MSs may shed a new light on clinical treatment of IVDD. [Display omitted] [ABSTRACT FROM AUTHOR]

The needle puncture model in rats has been accepted as an ordinary model to induce intervertebral disc degeneration (IVDD). However, the model primarily penetrated the whole intervertebral disc, resulting in injury to the nucleus pulposus (NP) and annulus fibrosus (AF). The intention of this research was to explore a minimally invasive approach through needle puncture of the AF percutaneously in rats. Twenty SD rats underwent puncture at Co8/9 via a 20 G percutaneous needle. The needle was slowly advanced perpendicular to the tail skin to penetrate the whole AF without damaging the NP limited by a hand-made sheath. The X-rays and magnetic resonance imaging T2 relaxation was evaluated at 1, 2, and 3 weeks to assess the disc height index and signal changes. Histological and immunohistochemical staining of the IVD were obtained under a light microscope. X-rays showed that the disc height had progressively narrowed to 49% of baseline 3 weeks after injury. magnetic resonance imaging evaluation demonstrated that the mean T2-weighted signal intensity at 3 weeks was 43% of that in the uninjured control group at the Co8/9 level. Histological staining demonstrated disorganized lamellae in the AF and decreased proteoglycan content and cellularity within the NP in the injured discs. The present research demonstrates a reliable and convenient approach to induce an AF tear in rats through percutaneous needle puncture. This model reduces harm to the experimental animals significantly while imitating the progressive degeneration process. More importantly, the model confirmed that AF damage alone could lead to IVDD and provided a research method for AF degeneration in IVDD. [ABSTRACT FROM AUTHOR]

Polysaccharide-based hydrogels have gained prominence due to their non-toxicity, biocompatibility, and structural adaptability for constructing tissue engineering scaffolds. Polysaccharide crosslinking is necessary for hydrogel stability in vivo. The periodate oxidation enables the modification of native polysaccharide characteristics for wound healing and tissue engineering applications. It produces dialdehydes, which are used to crosslink biocompatible amine-containing macromolecules such as chitosan, gelatin, adipic acid dihydrazide, silk fibroin, and peptides via imine/hydrazone linkages. Crosslinked oxidized ionic polysaccharide hydrogels have been studied for wound healing, cardiac and liver tissue engineering, bone, cartilage, corneal tissue regeneration, abdominal wall repair, nucleus pulposus regeneration, and osteoarthritis. Several modified hydrogel systems have been synthesized using antibiotics and inorganic substances to improve porosity, mechanical and viscoelastic properties, desired swelling propensity, and antibacterial efficacy. Thus, the injectable hydrogels provide a host-tissue-mimetic environment with high cell adhesion and viability, making them appropriate for scarless wound healing and tissue engineering applications. This review describes the oxidation procedure for alginate, hyaluronic acid, gellan gum, pectin, xanthan gum and chitosan, as well as the characteristics of the resulting materials. Furthermore, a critical review of scientific advances in wound healing and tissue engineering applications has been provided. [Display omitted] [ABSTRACT FROM AUTHOR]

Schematic diagram of the study on the dual mode of JTG-GelMA scaffold to promote the regeneration of degenerated intervertebral disc. [Display omitted] • Jintiange Capsule was used for the first time in the treatment of intervertebral disc degeneration. • The effects of hydrogel matrix hardness on the phenotype and growth of nucleus pulposus cells were reported. • The cellular and tissue mechanics in the process of intervertebral disc degeneration were discussed. • A rat disc degeneration model was established to simulate the changes of lumbar disc in human daily life. Diseases such as low back pain and disc protrusion, stemming from intervertebral disc degeneration, have emerged as notable global public health challenges. Researchers have dedicated considerable efforts to delaying the onset of intervertebral disc degeneration through timely intervention, thereby fostering the regeneration of degenerative intervertebral discs. In this investigation, an integration of traditional Chinese medicine theory with contemporary research methodologies was undertaken to devise a composite treatment regimen employing varied concentrations of artificial tiger bone powder (JTG) and GelMA gel. The effect of JTG-GelMA hydrogel on the regeneration of degenerative intervertebral discs was scrutinized via both in vitro and in vivo investigations. The results demonstrated that JTG-GelMA hydrogel promotes the regeneration of degenerative intervertebral discs through dual mechanisms of improving the matrix stiffness of NP cells and inhibiting ECM degradation. Furthermore, a positive correlation between the regenerative efficacy and JTG concentration was observed. This research introduces a novel approach for early intervention in intervertebral disc degeneration and furnishes a theoretical framework for the innovative utilization of traditional medicinal formulations. [ABSTRACT FROM AUTHOR]

[Display omitted] • The IL-32 expression is positively correlated with the severity of IDD. • IL-32 mediates matrix metabolism disorder in NP cells. • IL-32 regulates matrix metabolism in NP cells via the FAT4/MST/YAP axis. Extracellular matrix (ECM) metabolism disorders in the inflammatory microenvironment play a key role in the pathogenesis of intervertebral disc degeneration (IDD). Interleukin-32 (IL-32) has been reported to be involved in the progression of various inflammatory diseases; however, it remains unclear whether it participates in the matrix metabolism of nucleus pulposus (NP) cells. Therefore, this study aimed to investigate the mechanism of IL-32 on regulating the ECM metabolism in the inflammatory microenvironment. RNA-seq was used to identify aberrantly expressed genes in NP cells in the inflammatory microenvironment. Western blotting, real-time quantitative PCR, immunohistochemistry and immunofluorescence analysis were performed to measure the expression of IL-32 and metabolic markers in human NP tissues or NP cells treated with or without tumor necrosis factor-α (TNF-α). In vivo, an adeno-associated virus overexpressing IL-32 was injected into the caudal intervertebral discs of rats to assess its effect on IDD. Proteins interacting with IL-32 were identified via immunoprecipitation and mass spectrometry. Lentivirus overexpressing IL-32 or knocking down Fat atypical cadherin 4 (FAT4), yes-associated protein (YAP) inhibitor-Verteporfin (VP) were used to treat human NP cells, to explore the pathogenesis of IL-32. Hippo/YAP signaling activity was verified in human NP tissues. IL-32 expression was significantly upregulated in degenerative NP tissues, as indicated in the clinical samples. Furthermore, IL-32 was remarkably overexpressed in TNF-α-induced degenerative NP cells. IL-32 overexpression induced IDD progression in the rat model. Mechanistically, the elevation of IL-32 in the inflammatory microenvironment enhanced its interactions with FAT4 and mammalian sterile 20-like kinase1/2 (MST1/2) proteins, prompting MST1/2 phosphorylation, and activating the Hippo/YAP signaling pathway, causing matrix metabolism disorder in NP cells. Our results suggest that IL-32 mediates matrix metabolism disorders in NP cells in the inflammatory micro-environment via the FAT4/MST/YAP axis, providing a theoretical basis for the precise treatment of IDD. [ABSTRACT FROM AUTHOR]

Lumbar disc herniation is usually caused by the accumulation of long-term mechanical loads and sudden overload damage. Therefore, this study aims to illustrate how fatigue failure in lumbar spine segments is influenced by both cyclic loading magnitude and pre-existing damage. Eighty-six sheep intervertebral disc samples were divided into four groups to test the fatigue responses in healthy and damaged intervertebral discs. Both before and after fatigue loading, the specimens were performed on loading–unloading tests to analyze the viscoelasticity changes, while the specimens were performed on MRI examination to analyze the geometric and morphological changes. The Stress-Failure curve (SN curve) was examined, while the number of cycles to failure of damaged specimens was much smaller than that of healthy specimens at the same stress level during cyclic loading, and the relationship was approximately linear on a logarithmic scale. In addition, the healthy specimens will not accumulate fatigue failure if the compression force remains below 50% of the ultimate compressive tolerance (UTC). Before and after fatigue loading, the loading–unloading curves do not coincide and show obvious strain-rate-dependent viscoelastic characteristics, while the elastic modulus of the damaged specimen is significantly smaller. For magnetic resonance imaging, morphological changes included the changes of nucleus pulposus (NP) shape and area, while fatigue has a more significant effect on ruptured and herniated disc specimens. The dissipated energy of the intervertebral discs under cyclic loading was then calculated based on viscoelastic constitutive equations, which show that the load and preexisting damage both have significant effects on the dissipation rate. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). β-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. The expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing sh Arrb1 (LV-sh Arrb1) and overexpressing Arrb1 (LV-oe Arrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo , LV-oe Arrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. In the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD. [Display omitted] • ARRB1 protects intervertebral disc form degeneration. • Autophagy is associated with ARRB1-mediated mechanism inhibiting IVDD. • ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs. [ABSTRACT FROM AUTHOR]

• There are no effective treatments for intervertebral disc degeneration. • Isorhapontigenin delays IL-1β-induced senescence of nucleus pulposus cells and degradation of the extracellular matrix. • Isorhapontigenin inhibits intervertebral disc degeneration by regulating PI3K/AKT/mTOR-mediated autophagy pathway. • Isorhapontigenin can be used as a potential treatment for intervertebral disc degeneration. Intervertebral disc degeneration (IVDD), a common degenerative disc disease, is a major etiological factor for back pain, affecting a significant number of middle-aged and elderly individuals worldwide. Thus, IVDD is a major socio-economic burden. The factors contributing to the complex IVDD etiology, which has not been elucidated, include inflammation, oxidative stress, and natural aging. In particular, inflammation and aging of nucleus pulposus cells are considered primary pathogenic factors. Isorhapontigenin (ISO) is a polyphenolic compound commonly found in traditional Chinese herbs and grapes. We have demonstrated that ISO exerts anti-inflammatory and anti-aging effects and mitigates extracellular matrix (ECM) degradation. In this study, in vitro experiments revealed that, ISO delays aging and ECM degradation by promoting PI3K/AKT/mTOR-mediated autophagy. Meanwhile, in vivo experiments affirmed that ISO delays the progression of IVDD. [ABSTRACT FROM AUTHOR]

[Display omitted] • NP implantation induced pain behaviors and low Mg2+ content in serum and CSF. • L-TAMS alleviated pain behaviors and increased Mg2+ content of rats with NP. • L-TAMS inhibited spinal inflammatory response of rats with NP. • L-TAMS decreased spinal C-fiber responses and NR2B expression of rats with NP. • Pro-inflammatory cytokines rescued the effects of L-TAMS. We have reported neuro-inflammation is involved in radicular pain by enhancing the efficiency of pain synaptic transmission in spinal level. Recently, peers' studies have confirmed that magnesium deficiency leads to neuro-inflammation, thus contributes to memory and emotional deficits and pain hypersensitivity in antineoplastic agents treated rats. In this study, we explore the effect of oral application of magnesium- L -threonate (L-TAMS) in radicular pain induced by lumbar disc herniation (LDH) of rats and the possible mechanisms. Rat model of LDH was induced by autologous nucleus pulposus (NP) implantation. Mechanical and thermal pain thresholds were assessed by von Frey filaments and hotplate test respectively. L-TAMS was applied from drinking water at dosage of 604 mg/kg/day from 2 day before NP implantation and until the end of the experiment. Free Mg2+ content in serum and cerebrospinal fluid (CSF) was measured by calmagite chromometry. Synaptic transmission efficiency was determined by C-fiber evoked field potentials recorded by electrophysiologic recording in vivo. The activation of microglia in spinal dorsal horn was displayed by immunofluorescence staining and western blotting. The expressions of pro-inflammatory cytokines and glutamic N-methyl-D-aspartate receptor (NMDAR) subunits (NR2A, NR2B) were assessed by western blotting and enzyme-linked immunosorbent assay (ELISA) respectively. NP implantation induced mechanical allodynia and thermal hyperalgesia, accompanied by decreased Mg2+ concentration in serum and CSF which were both obscured by oral application of L-TAMS. L-TAMS inhibited spinal microglia activation and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) expression of rats with NP. L-TAMS decreased C-fiber evoked potentials and NR2B protein level in rats with NP, which were rescued by extra intrathecal delivery of TNF-α or IL-6 or IL-1β. Oral application of L-TAMS alleviates radicular pain by inhibiting neuro-inflammation dependent central sensitization of rats. [ABSTRACT FROM AUTHOR]

Limited studies examine the impact of presenting symptom duration on clinical outcomes in patients undergoing lumbar decompression (LD) in the ambulatory surgical center (ASC). The purpose of this study is to evaluate the influence of preoperative symptom duration defined as symptom onset greater than or less than 365 days on postoperative Patient-Reported Outcome Measures (PROMs) after undergoing LD in the ASC. The recent change from inpatient to outpatient spine surgery is driven by the cost reduction and increased patient satisfaction. Therefore, more data using patients coming from an ASC will help physicians with surgical planning and patient selection. Retrospective review. Patients who underwent lumbar decompression in the ambulatory surgical setting. Veterans Rand-12 Physical Composite Score (VR-12 PCS), Short Form-12 Physical Composite Score (SF-12 PCS), Patient-Reported Outcome Measurement Information System-Physical Function (PROMIS-PF), Visual Analog Scale-Back Pain (VAS-B), Visual Analog Scale-Leg Pain (VAS-L), and Oswestry Disability Index (ODI). A retrospective chart review was conducted from 4/2013 to 10/2023 to identify patients who underwent LD in the ASC using a single surgeon database that is prospectively maintained. IRB approval was petitioned and approved (ORA #23111509). Demographic and perioperative characteristics were collected from electronic medical records. Patient-reported outcome measures (PROMs) were requested preoperatively, at 6 weeks, and again at final follow-up appointments. Independent samples t-tests and chi-square tests were used for statistical analysis. A total of 311 patients were included, symptom duration >365 days n=118 and <365 days n= 193. Patient demographics include, mean age approximately 41.4 years. ASA Score does exhibit a slight difference with a mean of 1.71 for the >365 days group and 1.56 for the <365 days group (p=0.044). Both groups represented a presenting pathology of herniated nucleus pulposus, but central stenosis and foraminal stenosis were more prevalent in the >365 days group (80.5% and 77.1%, respectively) compared to the <365 days group (68.9% and 62.7%, respectively). Preop PROMS showed no significant differences. However, at 6 weeks significant differences between the <365 days group reporting lower pain scores compared to the >365 days group. At final Postop data significant differences in SF-12 PCS, VAS-B, VAS-L, and ODI, indicating that the <365 days group had better outcomes in terms of physical function and pain levels. The <365 days group achieved MCID more frequently than the >365 days group for VAS-B and ODI. In this retrospective study of 311 patients who underwent lumbar discectomy in an ambulatory surgery center, the influence of preoperative symptom duration on postoperative outcomes was evaluated. Two groups were compared: those with symptom durations less than 365 days and those exceeding 365 days. While both groups had similar average ages, patients with shorter symptom durations demonstrated superior outcomes at 6 weeks and final postoperative assessments, with lower pain levels and improved physical function. The study suggests that early surgical intervention may lead to better results in patients undergoing lumbar discectomy and would benefit from surgery in an ambulatory setting. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration (IVDD) is a prevalent condition contributing to back pain and disability. Periostin (POSTN) has emerged as a potential molecular marker and therapeutic target in IVDD, prompting further investigation into its role and mechanisms. This study employs bioinformatics analysis combined with experimental validation to explore the role of POSTN in IVDD. Gene expression datasets from the GEO database were analyzed to identify genes associated with IVDD, and the effects of POSTN on rat nucleus pulposus (NP) cells senescence and extracellular matrix (ECM) metabolism were assessed both in vitro and in vivo. Elevated POSTN expression was observed in degenerated discs from IVDD patients, correlating with disease severity. In vitro experiments demonstrated that POSTN promotes NP cells senescence and ECM metabolism in a dose- and time-dependent manner. In vivo studies confirmed that POSTN inhibition can ameliorate the progression of IVDD. Further mechanistic insights revealed that POSTN may exert its effects by activating the NF-κB and Wnt/β-catenin signaling pathways. POSTN plays a significant role in the pathogenesis of IVDD, with its upregulated expression closely linked to NP cells senescence and ECM metabolism. Targeting POSTN could offer a novel therapeutic strategy for IVDD. Additionally, the study predicts small molecules that may inhibit POSTN expression, providing potential candidates for the development of new drug treatments. • POSTN in IVDD: Diagnostic and therapeutic potential shown. • Role of POSTN: Explored through bioinformatics and validation. • POSTN promotes NP cell senescence and ECM metabolism. • POSTN inhibition slows IVDD progression. • Mechanistic insights: POSTN activates NF-κB and Wnt/β-catenin pathways, potential drug targets. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration is a clinical disease that reduces the quality of patient's life. The degeneration usually initiates in the nucleus pulposus (NP), hence the use of hydrogels represents a promising therapeutic approach. However, the viscoelastic nature of hydrogel and its ability to provide biomimetic architecture and biochemical cues influence the regeneration capability. This study focused on tuning the physical nature of a glycosaminoglycan hydrogel (κ-carrageenan) as well as the release kinetics of a chondrogenic factor (kartogenin - KGN) through physical cross-linking. For this, κ-carrageenan was cross linked with 2.5 % and 5 % potassium chloride (KCl) for 15 and 30 min and loaded with KGN molecule at 50 μM and 100 μM. The tight network structure with low water retention and degradation property was seen in hydrogel cross-linked with increased KCl concentration and time. However, optimal degradation along with NP mimicking viscoelastic nature was exhibited by 5 wt% KCl treated hydrogel (H3 hydrogel). All hydrogel groups exhibited burst KGN release at 24 h followed by a sustained release for 5 days. However, hydrogel cross-linked with 5 wt% KCl enhanced chondrogenic differentiation, mainly at lower KGN dose. In summary, this study shows the potential application of biomimetic KGN laden carrageenan hydrogel in NP regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder that is associated with considerable morbidity. However, there is currently no drug available that has a definitive therapeutic effect on IDD. In this study, we aimed to identify the molecular features and potential therapeutic targets of IDD through a comprehensive multiomics profiling approach. By integrating transcriptomics, proteomics, and ultrastructural analyses, we discovered dysfunctions in various organelles, including mitochondria, the endoplasmic reticulum, the Golgi apparatus, and lysosomes. Metabolomics analysis revealed a reduction in total phosphatidylcholine (PC) content in IDD. Through integration of multiple omics techniques with disease phenotypes, a pivotal pathway regulated by the lysophosphatidylcholine acyltransferase 1 (LPCAT1)-PC axis was identified. LPCAT1 exhibited low expression levels and exhibited a positive correlation with PC content in IDD. Suppression of LPCAT1 resulted in inhibition of PC synthesis in nucleus pulposus cells, leading to a notable increase in nucleus pulposus cell senescence and damage to cellular organelles. Consequently, PC exhibits potential as a therapeutic agent, as it facilitates the repair of the biomembrane system and alleviates senescence in nucleus pulposus cells via reversal of downregulation of the LPCAT1-PC axis. [ABSTRACT FROM AUTHOR]