Low-dose celecoxib-loaded PCL fibers reverse intervertebral disc degeneration by up-regulating CHSY3 expression.

Intervertebral disc degeneration (IDD) has been identified as one of the predominant factors leading to persistent low back pain and disability in middle-aged and elderly people. Dysregulation of Prostaglandin E2 (PGE2) can cause IDD, while low-dose celecoxib can maintain PGE2 at the physiological level and activate the skeletal interoception. Here, as nano fibers have been extensively used in the treatment of IDD, novel polycaprolactone (PCL) nano fibers loaded with low-dose celecoxib were fabricated for IDD treatment. In vitro studies demonstrated that the nano fibers had the ability of releasing low-dose celecoxib slowly and sustainably and maintain PGE2. Meanwhile, in a puncture-induced rabbit IDD model, the nano fibers reversed IDD. Furthermore, low-dose celecoxib released from the nano fibers was firstly proved to promote CHSY3 expression. In a lumbar spine instability-induced mouse IDD model, low-dose celecoxib inhibited IDD in CHSY3wt mice rather than CHSY3-/- mice. This model indicated that CHSY3 was indispensable for low-dose celecoxib to alleviate IDD. In conclusion, this study developed a novel low-dose celecoxib-loaded PCL nano fibers to reverse IDD by maintaining PGE2 at the physiological level and promoting CHSY3 expression.

Fever as a rare combined symptom of degenerative cervical myelopathy: a case report and literature review.

A 60-year-old male patient complained of weakness of both legs for one year, intermittent fever for two months, up to 38.0 °C. Physical examination showed bilateral hyperreflexia of knee tendon and positive Hoffman sign on the right side. MR imaging of the cervical spine showed central herniation of the cervical 5-7 disc and compression of the spinal cord. The WBC was normal, C-reactive protein was 24.42mg/l, ESR was 55mm/h, TB antibody, anti acid staining and T-SPOT were negative. Autoantibody was negative and thyroid function was normal. The JOA score was 9 points. During the operation, the herniated disc tissue was taken out for pathological examination and bacterial culture. The posterior longitudinal ligament was removed and no abscess was found. The symptom of asthenia in both legs was relieved and fever disappeared. No growth of aerobe, anaerobe or tubercle bacilli was found in the culture of resected tissue. One year after the operation, the fever did not recur, JOA score increased to 14 points, and MR imaging showed no protrusion in cervical spinal canal. In this case, the fever disappeared after the operation for cervical spondylosis, which may be a special manifestation of sympathetic nerve stimulation or autonomic dysfunction by chronic compression of spinal cord.

Predictive value of vertebral Hounsfiled Unit for titanium mesh cage subsidence following ACCF surgery.

OBJECTIVE: To investigate the predictive value of cervical Hounsfiled Unit (HU) values for postoperative titanium mesh cage (TMC) subsidence. METHODS: Clinical data of patients who underwent ACCF surgery for degenerative cervical myelopathy between January 2016 and August 2018 were analyzed. Among the 126 patients included, 74 were male and 52 were female, with a mean age of 61.0 ± 9.9 years. The mean follow-up was 37.1 ± 11.2 months. Preoperative vertebral HU values were measured and the degree of TMC subsidence during follow-up was assessed. Patients were divided into two groups according to the presence or absence of subsidence: the subsidence group and the control group. Vertebral HU values were compared between the two groups, and correlation analysis was performed between HU values and TMC subsidence values. In addition, the predictive value and threshold of HU were analyzed by using ROC. RESULTS: There were 22 patients (14 males and 8 females) who developed TMC subsidence (subsidence group), while 104 patients (60 males and 44 females) did not develop TMC subsidence (control group) during follow-up. Comparative analysis of demographic characteristics between the two groups showed no significant differences in gender, age, BMI, diagnosis, surgical levels, and follow-up duration (all P values > 0.05). There was a significant difference in mean HU between the subsidence group (287.6 ± 49.6) and the control group (342.4 ± 61.4) (t = -3.92, P < 0.01). In the subsidence group, there was a significant correlation between subsidence values and HU values (r = -0.52, P = 0.01), whereas no such correlation was observed in the control group (r = - 0.07, P = 0.51). ROC analysis indicated that vertebral HU values could potentially be used to predict subsidence after ACCF, with an area under the ROC curve of 0.77 (95% CI 0.66-0.87; P < 0.01). The optimal HU threshold was found to be 298, with a sensitivity of 76.9% and specificity of 68.2%. CONCLUSION: Preoperative vertebral HU values were associated with postoperative TMC subsidence. Vertebral HU may be a valuable predictor of postoperative subsidence.

A Pilot Study of a Finger Kinematic Parameter-Based Tool for Evaluating Degenerative Cervical Myelopathy.

STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: To evaluate the effectiveness of a novel finger Kinematic Parameter-Based Tool in the grip and release (G&R) test for assessing degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: The development and progression of DCM symptoms are gradual and obscure. Although previous studies have objectively evaluated hand movements specific to myelopathy using the G&R test, virtual reality, or wearable sensors, these methods have limitations, such as limited discrimination or inconvenience for simple screening. Consequently, there is a need to develop effective screening methods. MATERIALS AND METHODS: Totally, 297 asymptomatic volunteers and 258 DCM patients were enrolled. This system comprises a wearable acceleration/gyro sensor. The acceleration/gyro sensor was placed on the little finger of the participants to perform 40 cycles of full-range G&R as quickly as possible. The collected data were then transformed into kinematic parameters using sensor-based software and R studio software (version: RStudio 2022.07.2+576, Boston, USA). Gender, age, and body mass index (BMI) subgroups (classified as BMI<18.5-below normal weight; 18.5≤BMI<25-normal weight group; BMI≥25-overweight group) were matched as predictor variables, and 201 pairs were matched. Nonparametric analysis using the Mann-Whitney U test was used for diagnosing the differences between the two groups, and Kruskal-Wallis's test followed by the Mann-Whitney U test was used for analyzing the differences among three different age groups (<40, 41-60, and >60 yr group). The cut-off value of 10s G&R cycles and a combined parameter were determined using receiver operating characteristics curve analysis, area under the curve, and Youden index. RESULTS: The authors found that little finger kinematic parameters were significantly lower in DCM patients than in asymptomatic participants. The optimal diagnostic indicator appeared to be the average of the top 10 linear accelerations with an area under the curve of 0.923. CONCLUSION: The Finger Kinematic Test System is an objective, practical, and quantitative utility that appears to have the capacity to diagnose and evaluate the severity of DCM. LEVEL OF EVIDENCE: 3.

Metformin-grafted polycaprolactone nanoscaffold targeting sensory nerve controlled fibroblasts reprograming to alleviate epidural fibrosis.

Epidural fibrosis (EF), associated with various biological factors, is still a major troublesome clinical problem after laminectomy. In the present study, we initially demonstrate that sensory nerves can attenuate fibrogenic progression in EF animal models via the secretion of calcitonin gene-related peptide (CGRP), suggesting a new potential therapeutic target. Further studies showed that CGRP could inhibit the reprograming activation of fibroblasts through PI3K/AKT signal pathway. We subsequently identified metformin (MET), the most widely prescribed medication for obesity-associated type 2 diabetes, as a potent stimulator of sensory neurons to release more CGRP via activating CREB signal way. We copolymerized MET with innovative polycaprolactone (PCL) nanofibers to develop a metformin-grafted PCL nanoscaffold (METG-PCLN), which could ensure stable long-term drug release and serve as favorable physical barriers. In vivo results demonstrated that local implantation of METG-PCLN could penetrate into dorsal root ganglion cells (DRGs) to promote the CGRP synthesis, thus continuously inhibit the fibroblast activation and EF progress for 8 weeks after laminectomy, significantly better than conventional drug loading method. In conclusion, this study reveals the unprecedented potential of sensory neurons to counteract EF through CGRP signaling and introduces a novel strategy employing METG-PCLN to obstruct EF by fine-tuning sensory nerve-regulated fibrogenesis.

Application of TVD-Net for sagittal alignment and instability measurements in cervical spine radiographs.

BACKGROUND: Cervical spinal malalignment and instability are frequently occurring pathological conditions involving neck pain, radiculopathy, and myelopathy, often requiring surgical intervention. Accurate assessment of cervical alignment and instability are essential in surgical planning and evaluating postoperative outcomes. PURPOSE: To automatically measure the sagittal alignment and instability of the cervical spine, we develop a novel deep-learning model by detecting landmarks on cervical radiographs. METHODS: We introduce the transformer-embedded residual network (ResNet) as the network's core to automatically identify vertebral landmarks on digital and film-transformed cervical radiographs, and simultaneously measure the segmental Cobb angle and horizontal displacement. A Transformer Module was embedded into the latent space to extract the relationship between different vertebrae. Then a Rotating Attention Module was integrated between the encoder-decoder pairs to highlight the key points and maintain more details. Finally, a Vector Loss Module was proposed to restrain the orientation of the adjacent vertebra to reduce misdetection. All images were obtained from local hospital. Digital images were split into training, validation, and test subsets (896, 225, and 353 images, respectively). Likewise, film-transformed images were split into 404, 115, and 150 images, respectively. The results of the model were compared with manual measurements. RESULTS: Our deep learning algorithm achieved mean absolute difference (MAD) at a level of 2.20° and 2.33°, symmetric mean absolute error(SMAPE)at 16.63% and 19.35%, respectively, when measuring Cobb angle on digital images and films. On evaluating cervical instability, the diagnostic accuracy, sensitivity, specificity, precision, and F1-score evaluation metrics were calculated. The corresponding values were 89.80%, 86.49%, 90.68%, 71.11%, and 78.05% on digital images, and 90.00%, 83.78%, 91.15%, 75.61%, and 79.49% on film-transformed images, which were comparable to experienced surgeons. Visualization results demonstrated robust effectiveness in subjects with severe osteophytes or artifacts. CONCLUSION: This study presents a novel and efficient deep-learning model to assist landmarks identification and angulation and displacement calculation on lateral cervical spine radiographs, and demonstrates excellent accuracy in measuring cervical alignment and sound sensitivity and specificity in cervical instability diagnosis. It should be helpful for future research and clinical applications.

Continuous release of mefloquine featured in electrospun fiber membranes alleviates epidural fibrosis and aids in sensory neurological function after lumbar laminectomy.

Recurrent low back pain after spinal surgeries, such as lumbar laminectomy, is a major complication of excessive epidural fibrosis. Although multiple preclinical and clinical methods have been aimed at ameliorating epidural fibrosis, their safety and efficacy remain largely unclear. Single implanted electrospun fibrous membranes provide physical barriers that can decrease tissue fibrosis after surgery; however, they also trigger local inflammation due to the implantation of a foreign body, thus subsequently attenuating their anti-fibrosis properties. Here, we designed a strategy that permits easy incorporation of mefloquine into polylactic acid membranes, and stable long-term mefloquine release, to potentially improve anti-fibrosis effects and relieve or prevent low back pain. The electrospun fibrous membranes grafted with mefloquine showed a well-controlled early temporary peak release, and secondary drug release occurred smoothly over several weeks. Histopathological and histomorphometric results indicated that the drug-loaded membranes had excellent anti-fibrosis effects after laminectomy in rats. Inflammation and neovascularization at the surgical site indicated that the mefloquine-grafted electrospun fibrous membranes provided sustained anti-inflammatory outcomes while effectively alleviating associated neuropathic pain hypersensitivity. In summary, our study indicated that polylactic acid-mefloquine grafted electrospun fibrous membranes may be a potential local agent to mitigate epidural fibrosis and support sensory neurological function after laminectomy, thereby potentially improving patients' postoperative outcomes.

Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis.

Sensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio-synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene-related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity-modifying protein 1 (RAMP1) and cyclic AMP response element-binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.

Increased Expression of Integrin Alpha 6 in Nucleus Pulposus Cells in Response to High Oxygen Tension Protects against Intervertebral Disc Degeneration.

The destruction of the low oxygen microenvironment in nucleus pulposus (NP) cells played a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). The purpose of this study was to determine the potential role of integrin alpha 6 (ITG α6) in NP cells in response to high oxygen tension (HOT) in IVDD. Immunofluorescence staining and western blot analysis showed that the levels of ITG α6 expression were increased in the NP tissue from IVDD patients and the IVDD rat model with mild degeneration, which were reduced as the degree of degeneration increases in severity. In NP cells, the treatment of HOT resulted in upregulation of ITG α6 expression, which could be alleviated by blocking the PI3K/AKT signaling pathway. Further studies found that ITG α6 could protect NP cells against HOT-induced apoptosis and oxidative stress and protect NP cells from HOT-inhibited ECM protein synthesis. Upregulation of ITG α6 expression by HOT contributed to maintaining NP tissue homeostasis through the interaction with hypoxia-inducible factor-1α (HIF-1α). Furthermore, silencing of ITG α6 in vivo could obviously accelerate puncture-induced IVDD. Taken together, these results revealed that the increase of ITG α6 expression by HOT in NP cells might be a protective factor in IVD degeneration as well as restore NP cell function.

Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration.

Intervertebral disc (IVD) degeneration is known to aggravate with age and oxidative stress is implicated in the pathogenesis of many age-related diseases. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) can confer adaptive protection against oxidative and proteotoxic stress in cells. In this study, we assessed whether Nrf2 can protect against oxidative stress in nucleus pulposus (NP) cells. In addition, we investigated Nrf2 expression in NP tissue samples from patients with different degrees of IVD degeneration and a mouse model of aging and IVD degeneration and the influence of H2O2-induced oxidative stress on autophagic pathways in NP cells. Autophagy was assessed by measuring levels of autophagy-related protein (ATG) family members and the autophagic markers, p62 and LC3. We found that expression of Nrf2 progressively decreased in human NP tissue samples of patients with increasing degrees of IVD degeneration. Nrf2 deficiency leads to the degeneration of IVDs during aging. Nrf2 knockout also aggravates IVD degeneration and reduces autophagic gene expression in an induced mouse model of IVD degeneration. The detrimental effects of H2O2-induced oxidative stress were increased in autophagy-deficient cells via reduced expression of Atg7 and the Keap1-Nrf2-p62 autophagy pathway. Taken together, these results suggest that excessive oxidative stress causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response activated by a Keap1-Nrf2-p62 feedback loop in IVD degeneration.

Tantalum-coated pedicle screws enhance implant integration.

Because titanium alloy (Ti) has the natural advantage of a low elastic modulus, it has become the most commonly used material for the manufacturing of pedicle screws. However, its poor shear strength and osteogenic ability are undesirable properties. The superior osteoinductivity demonstrated by tantalum (Ta) in oral and maxillofacial surgery and joint surgery leads us to assume that the tantalum-coated pedicle screws may have better osteogenic properties and bone anchoring strength. To verify this hypothesis, MC3T3-E1 cells and human mesenchymal stem cells (hBMSCs) were seeded on the surface of Ta and Ti disks to compare the effects of two different metals on cell adhesion, proliferation, and differentiation. At the same time, we observed the inhibitory effect of Ta on osteoclasts. As an in vivo study, conventional Ti pedicle screws and Ta-coated screws were implanted in bilateral pedicles of Bama pigs. The results showed that compared to titanium, tantalum promoted greater cell adhesion and proliferation and improved the level of hBMSC mineralization, and Ta-coated screws exerted an inhibitory effect on osteoclasts. More importantly, we found that the effect of tantalum on osteogenic differentiation was mediated through the Wnt/ß-catenin and TGF-ß/smad signaling pathways. Ta-coated screws significantly promoted trabecular bone growth compared with Ti as evidenced by micro-CT, histology and biomechanical examination. Our study clearly indicated that tantalum was a superior promoter of osteogenesis and proved that tantalum coating is an effective improvement for titanium alloy implants.

Combined Anterior-Posterior Fixation and Fusion for Completely Dislocated Hangman's Fracture: A Retrospective Analysis of 11 Cases.

STUDY DESIGN: Retrospective clinical study. PURPOSE: To evaluate the effectiveness and feasibility of combined anterior-posterior fixation and fusion for the treatment of completely dislocated hangman's fracture. SUMMARY OF BACKGROUND DATA: A completely dislocated hangman's fracture describes the complete anterior displacement of the C2 vertebral body onto the C3 body. This type of fracture is exceptionally unstable, and for which the management is challenging. Specific treatment strategies need to be further clarified. METHODS: From January 2003 to January 2012, 11 patients with completely dislocated hangman's fracture underwent combined anterior-posterior fixation and fusion at our institution; an anterior-posterior approach was used in 9 patients, and an anterior-posterior-anterior approach was used in 2 patients. The operative time, hospital duration, neurological improvement, fusion rate, and complications were assessed. RESULTS: The operation times of the 2 anterior-posterior-anterior surgeries (165 and 210 min) were longer than the anterior-posterior approach surgeries (mean, 133 min; range: 110-155 min). The average hospital duration was 8.5 days (range: 7.0-13.0 d). Postoperative reduction and solid fusion were achieved in all patients. Neurological status was significantly improved, as the mean Japanese Orthopedic Association (JOA) score significantly increased from a preoperative score of 8.9±1.7 to 14.6±1.6 at the final follow-up (P<0.01). The mean neurological recovery rate was 51%. Moderate postoperative neck pain occurred in 2 patients, which was relieved after 2 months of conservative treatment with oral celecoxib. The mean visual analog scale pain score was 1.4±0.8 at the last assessment. Hoarseness was found after surgery in 1 patient who recovered 1 month later without any treatment. No graft-related or plate-related complications occurred during the entire follow-up period. CONCLUSIONS: Combined anterior-posterior fixation and fusion is an effective and safe treatment for completely dislocated hangman's fracture.

Inflammatory cytokines induce caveolin-1/ß-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway.

OBJECTIVES: Apoptosis of nucleus pulposus (NP) cells is a major cause of intervertebral disc degeneration. To elucidate relationships between caveolin-1 and cytokine-induced apoptosis, we investigated the role of caveolin-1 in cytokine-induced apoptosis in rat NP cells and the related signalling pathway. MATERIALS AND METHODS: Rat NP cells were treated with interleukin (IL)-1ß or tumour necrosis factor alpha (TNF-α), and knockdown of caveolin-1 and ß-catenin was achieved using specific siRNAs. Then, apoptotic level of rat NP cells and expression and activation of caveolin-1/ß-catenin signalling were assessed by flow cytometric analysis, qRT-PCR, western blotting and luciferase assays. The relationship between the mitogen-activated protein kinase (MAPK) pathway and caveolin-1 promoter activity was also determined by luciferase assays. RESULTS: IL-1ß and TNF-α induced apoptosis, upregulated caveolin-1 expression and activated Wnt/ß-catenin signalling in rat NP cells, while the induction effect of cytokines was reversed by caveolin-1 siRNA and ß-catenin siRNA. Promotion of rat NP cell apoptosis and nuclear translocation of ß-catenin induced by caveolin-1 overexpression were abolished by ß-catenin siRNA. Furthermore, pretreatment with a p38 MAPK inhibitor or dominant negative-p38, blocked cytokine-dependent induction of caveolin-1/ß-catenin expression and activity. CONCLUSIONS: The results revealed the role of p38/caveolin-1/ß-catenin in inflammatory cytokine-induced apoptosis in rat NP cells. Thus, controlling p38/caveolin-1/ß-catenin activity seemed to regulate IL-1ß- and TNF-α-induced apoptosis in the NP during intervertebral disc degeneration.