Selective cargo sorting in stem cell-derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration.

BACKGROUND: Growing evidence has suggested the role of stem cell-derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered that miRNAs containing specific motifs are selectively sorted into intraluminal vesicles within mesenchymal stem cells (MSCs) in response to oxidative stress. METHODS: Analysis of miRNA cargoes in sEVs derived from normal MSCs (C-sEVs) or stressed MSCs (T-sEVs) was conducted using miRNA sequencing. Differential expressed miRNAs in sEVs and the identification of motifs were evaluated through bioinformatics analysis. Protein binding was assessed using immunofluorescent staining and immunoprecipitation analysis. Additionally, RNA pull down and RNA immunoprecipitation (RIP) immunoprecipitation were employed to determine the binding between miRNAs and proteins. The effects of C-sEVs and T-sEVs on IVDD were compared by detecting the expression levels of phenotypic genes in vitro or histological evaluation in vivo. RESULTS: The sorting process of miRNAs is mediated by the nucleocytoplasmic transport of heterogeneous nuclear ribonucleoproteins, which in turn facilitates the phosphorylation of SNAP25 and promotes the transport and secretion of sEVs. Additionally, CHMP1B plays a role in membrane repair and protects against cell ferroptosis upon oxidative stress, concurrently affecting the release of sEVs. Notably, stem cell-derived sEVs associated with ferroptosis impair the therapeutic efficacy for IVDD. However, the application of engineered sEVs containing a specific miRNA inhibitor exhibits the potential to reinstate the therapeutic efficacy for IVDD both in vitro and in vivo. CONCLUSIONS: Taken together, our findings shed light on the mechanism of miRNAs sorting into sEVs and offer new insights for the optimization of sEV-based treatments during intervertebral disc regeneration. regeneration.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.Abbreviations: 3-MA: 3-methyladenine; Baf-A1: bafilomycin A1; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; DNM1L/DRP1: dynamin 1 like; EdU: 5-Ethynyl-2'-deoxyuridine; HE: hematoxylin-eosin; IDD: intervertebral disc degeneration; IL1B/IL-1ß: interleukin 1 beta; IL6: interleukin 6; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MKI67/Ki67: marker of proliferation Ki-67; LBP: low back pain; MMP: mitochondrial membrane potential; MFN1: mitofusin 1; MFN2: mitofusin 2; MFF: mitochondrial fission factor; NP: nucleus pulposus; NLRX1: NLR family member X1; OMA1: OMA1 zinc metallopeptidase; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxidative species; SASP: senescence-associated secretory phenotype; SA-GLB1/ß-gal: senescence-associated galactosidase beta 1; SO: safranin o; TBHP: tert-butyl hydroperoxide; TP53/p53: tumor protein p53; SLC39A7/ZIP7: solute carrier family 39 member 7; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23.

Sequential Correction versus Conventional Correction for Severe and Rigid Kyphoscoliosis: A Retrospective Case Control Study.

OBJECTIVE: Conventional correction techniques were challenging and of high risk of neurological complications for the correction of severe and rigid kyphoscoliosis. A new technical note we developed and named as sequential correction, was used to treat severe and rigid kyphoscoliosis. The present study was to compare the clinical outcomes of sequential correction versus conventional correction for the treatment of severe and rigid kyphoscoliosis. METHODS: This is a respectively case-control study. Between January 2014 and December 2019, 36 adults underwent the surgical correction of severe and rigid kyphoscoliosis and were included in the present study. Among them, 20 adults underwent conventional correction, 16 adults underwent sequential correction. Major curve Cobb angle, kyphotic angle, coronal imbalance, and sagittal vertical axis were compared between two groups. The patient-reported health-related quality of life outcomes, including the Oswestry disability index score, and SRS-22 questionnaire, were recorded. Independent samples t-test, Mann-Whitney U test, and Wilcoxon signed-rank test, were used to compare the differences between two groups according to the results of normal distribution test. RESULTS: In conventional correction group, the mean major curve Cobb angle was 122.50° preoperatively, 40.35° immediately after surgery, and 43.95° at final follow-up postoperatively; the mean kyphotic angle was 97.45° preoperatively, 34.45° immediately after surgery, and 38.30° at final follow-up postoperatively. In the sequential correction group, the mean major angle was 134.44° preoperatively, 44.56° immediately after surgery, and 46.25° at final follow-up postoperatively; the mean kyphotic angle was 112.31° preoperatively, 39.00° immediately after surgery, and 40.38° at final follow-up postoperatively. The mean major curve Cobb angle and kyphotic angle of both groups were improved significantly, while there were no significant differences between two groups (p > 0.001). Improved self-reported quality of life scores were achieved postoperatively and at final follow-up postoperatively, and there were no significant differences between the two groups. The total complication rate of the patients underwent conventional correction was 55%, and the total complication rate of the patients underwent sequential correction was 43.75%. The complication rate of the two groups showed no significant difference. CONCLUSIONS: Sequential correction is an excellent and safe treatment for severe and rigid kyphoscoliosis in adults, with similar clinical outcomes with conventional correction. The total complication rate of the patients who underwent sequential correction was slightly lower than conventional correction.

Sequential correction of severe and rigid kyphoscoliosis: a new technical note and preliminary results.

OBJECTIVE: The present study is to evaluate the clinical outcomes of the sequential correction of severe and rigid kyphoscoliosis. METHODS: Between January 2014 and December 2020, 27 adults with severe and rigid kyphoscoliosis underwent sequential correction combined with posterior grade 4 or grade 5 spinal osteotomy. Radiological parameters, including the major curve Cobb angle, kyphotic angle, coronal imbalance, and sagittal vertical axis (SVA), were compared. Patient self-reported health-related quality of life (HRQOL) scores were used to evaluate clinical outcomes. RESULTS: The mean major curve Cobb angle improved from 134.30 ± 13.24° to 44.48 ± 9.34° immediately after surgery and to 46.11 ± 8.94° at the final follow-up. The mean kyphotic angle improved from 112.15 ± 20.28° to 38.63 ± 15.00° immediately after surgery and to 39.85 ± 14.92° at the final follow-up. The mean preoperative major curve Cobb angle of grade 5 spinal osteotomy group was higher than that of grade 4 spinal osteotomy group. Coronal imbalance and SVA slightly improved. The patient self-reported HRQOL scores improved postoperatively and at the final follow-up. Activity, appearance and total scores of the SRS-22 of the grade 5 spinal osteotomy group at the final follow-up were significantly better than those of the grade 4 spinal osteotomy group. CONCLUSIONS: Sequential correction combined with posterior grade 4 or grade 5 spinal osteotomies is an excellent and safe treatment for severe and rigid kyphoscoliosis in adults. Sequential correction combined with posterior grade 5 spinal osteotomies can be used to correct severe and rigid kyphoscoliosis with higher major curve Cobb angle.

The involvement of DDX3X in compression-induced nucleus pulposus pyroptosis.

OBJECTIVE: A study has been conducted to investigate the relationship between DDX3X and nucleus pulposus (NP) pyroptosis. METHODS: DDX3X and pyroptosis-related proteins (Caspase-1, Full-length GSDMD, Cleaved GSDMD) were measured in compression-induced human NP cells and tissue. DDX3X was overexpressed or knocked down by gene transfection. The expressions of NLRP3, ASC, and pyroptosis-related proteins were detected by Western blot assay. IL-1ß and IL-18 were detected by ELISA. HE staining and immunohistochemistry were used to observe the expression of DDX3X, NLRP3, and Caspase-1 in the rat model of compression-induced disc degeneration. RESULTS: DDX3X, NLRP3, and Caspase-1 were highly expressed in degenerated NP tissue. Overexpression of DDX3X induced pyroptosis in NP cells and increased levels of NLRP3, IL-1ß, IL-18, and pyroptosis-related proteins. Knockdown of DDX3X showed an opposite trend to overexpression of DDX3X. The NLRP3 inhibitor CY-09 effectively prevented the up-regulation of the expression of IL-1ß, IL-18, ASC, Pro-caspase-1, Full-length GSDMD, and Cleaved GSDMD. Increased expression of DDX3X, NLRP3, and Caspase-1 was observed in the rat model of compression-induced disc degeneration. CONCLUSION: Our study showed that DDX3X mediates pyroptosis of NP cells by upregulating NLRP3 expression, which ultimately leads to intervertebral disc degeneration (IDD). This discovery deepens the understanding of IDD pathogenesis and provides a promising and novel therapeutic target for IDD.

Augmenting Intracellular Cargo Delivery of Extracellular Vesicles in Hypoxic Tissues through Inhibiting Hypoxia-Induced Endocytic Recycling.

As mesenchymal stem-cell-derived small extracellular vesicles (MSC-sEVs) have been widely applied in treatment of degenerative diseases, it is essential to improve their cargo delivery efficiency in specific microenvironments of lesions. However, the interaction between the microenvironment of recipient cells and MSC-sEVs remains poorly understood. Herein, we find that the cargo delivery efficiency of MSC-sEVs was significantly reduced under hypoxia in inflammaging nucleus pulposus cells due to activated endocytic recycling of MSC-sEVs. Hypoxia-inducible factor-1 (HIF-1)-induced upregulated RCP (also known as RAB11FIP1) is shown to promote the Rab11a-dependent recycling of internalized MSC-sEVs under hypoxia via enhancing the interaction between Rab11a and MSC-sEV. Based on this finding, si-RCP is loaded into MSC-sEVs using electroporation to overcome the hypoxic microenvironment of intervertebral disks. The engineered MSC-sEVs significantly inhibit the endocytic recycling process and exhibit higher delivery efficiency under hypoxia. In a rat model of intervertebral disk degeneration (IDD), the si-RCP-loaded MSC-sEVs successfully treat IDD with improved regenerative capacity compared with natural MSC-sEV. Collectively, the findings illustrate the intracellular traffic mechanism of MSC-sEVs under hypoxia and demonstrate that the therapeutic capacity of MSC-sEVs can be improved via inhibiting endocytic recycling. This modifying strategy may further facilitate the application of extracellular vesicles in hypoxic tissues.

G3BP1 coordinates lysophagy activity to protect against compression-induced cell ferroptosis during intervertebral disc degeneration.

Lysophagy is a form of selective autophagy to remove unwanted lysosomes. However, its role in the pathogenesis of intervertebral disc degeneration (IDD) remains unclear. We intended to investigate the relationship between lysophagy and ferroptosis, as well as the potential involved molecules during IDD. Human nucleus pulposus (NP) cells were obtained from clinical patients. The protein levels, protein colocalization and cellular reactive oxygen species levels were assessed by western blotting, immunofluorescence analysis, immunoprecipitation and flow cytometry, respectively. The in vivo experiments were conducted based on the needle puncture-induced IDD model in rats. Compression pressure induces the lysophagy inactivation and lysosomal damage, resulting in iron overload and ferroptosis in human NP cells. Notably, Ras GTPase-activating protein-binding proteins 1 (G3BP1) resides at lysosomes to coordinate lysophagy activity mainly via the function of G3BP1/TSC2 complex. Dysfunction of G3BP1/TSC2 complex accelerates the lysosomal damage and ferroptosis in NP cells. Besides, inhibition of mTOR signalling ameliorates lysosomal damage and protects against cell ferroptosis. The in vivo experiments also demonstrate that the G3BP1/mTOR signalling is involved in the progression of IDD. These findings illustrate the relationship between lysophagy and compression-induced cell ferroptosis. It also indicates the positive role of G3BP1 and may provide potential targets for IDD treatment.

Sequential correction using satellite rod for the treatment of severe rigid spinal deformity: a retrospective study of 19 cases.

OBJECTIVES: The purpose of this study was to evaluate the effectiveness of sequential correction using satellite rod in patients with severe rigid spinal deformity undergoing posterior-only PVCR. METHODS: 19 patients with severe rigid spinal deformity who underwent PVCR at our center from January 2014 to December 2019 were reviewed. Radiographic measurements, including major coronal Cobb angle, kyphotic curve angle, coronal and sagittal balance were measured. Clinical results were noted, including the SRS-22 questionnaire, the Oswestry Disability Index score, and complications. RESULTS: Total 19 patients were followed at least 2 years. The mean coronal Cobb angle decreased from 122.7° ± 13.17° to 57.89° ± 8.65° postoperatively, and to 58.42° ± 8.98° at final follow-up. Correction rate is 52.8%. The kyphotic curve angle improved from 102.2° ± 17.05° preoperatively to 39.68° ± 13.67° postoperatively, and to 37.74° ± 12.14° at final follow-up. Correction rate is 61.2%. Compared to preoperative results, apex vertebral translation, ODI and SRS-22 were significantly improved at the final follow-up. CONCLUSIONS: For patients with severe rigid spinal deformities, sequential correction with an auxiliary satellite rod can effectively reduce surgical difficulty and improve correction rate.

Distal adding-on after surgery in Lenke 5C adolescent idiopathic scoliosis: clinical and radiological outcomes.

BACKGROUND: To evaluate the incidence and risk factors of postoperative distal adding-on in patients with Lenke 5C adolescent idiopathic scoliosis (AIS). More accurate selection criteria for the lower instrumented vertebra (LIV) should be confirmed to prevent distal adding-on. METHODS: Forty-six patients with Lenke 5C AIS who underwent posterior fusion were enrolled in the study. Patients were allocated into adding-on and no adding-on groups. Demographic data, clinical data, and radiographic parameters were recorded and compared. RESULTS: Postoperative distal adding-on occurred in eight patients (17.4%) during follow-up. Demographic data, clinical data, and baseline radiographic parameters of the two groups were not significantly different. The postoperative thoracolumbar (TL) or lumbar (L) Cobb angle, LIV translation, and LIV + 1 translation were higher in the adding-on group than those in the no adding-on group, while the postoperative coronal imbalance of the adding-on group was lower than that of the no adding-on group. The level difference of last barely touched vertebra (LBTV) and last substantial touched vertebra (LSTV) with LIV were higher in the adding-on group than in the no adding-on group. CONCLUSION: Postoperative TL/L curve, postoperative LIV translation, postoperative LIV + 1 translation, and postoperative coronal imbalance were determined as risk factors for postoperative distal adding-on in patients with Lenke 5C AIS. Moreover, LIV selection of LBTV-1 or LSTV-1 may cause a higher risk of postoperative distal adding-on.

Applications of Mixed Reality Technology in Orthopedics Surgery: A Pilot Study.

Objective: The aim of this study is to explore the potential of mixed reality (MR) technology in the visualization of orthopedic surgery. Methods: The visualization system with MR technology is widely used in orthopedic surgery. The system is composed of a 3D imaging workstation, a cloud platform, and an MR space station. An intelligent segmentation algorithm is adopted on the 3D imaging workstation to create a 3D anatomical model with zooming and rotation effects. This model is then exploited for efficient 3D reconstruction of data for computerized tomography (CT) and magnetic resonance imaging (MRI). Additionally, the model can be uploaded to the cloud platform for physical parameter tuning, model positioning, rendering and high-dimensional display. Using Microsoft's HoloLens glasses in combination with the MR system, we project and view 3D holograms in real time under different clinical scenarios. After each procedure, nine surgeons completed a Likert-scale questionnaire on communication and understanding, spatial awareness and effectiveness of MR technology use. In addition to that, the National Aeronautics and Space Administration Task Load Index (NASA-TLX) is also used to evaluate the workload of MR hologram support. Results: 1) MR holograms can clearly show the 3D structures of bone fractures, which improves the understanding of different fracture types and the design of treatment plans; 2) Holograms with three-dimensional lifelike dynamic features provide an intuitive communication tool among doctors and also between doctors and patients; 3) During surgeries, a full lesion hologram can be obtained and blended in real time with a patient's virtual 3D digital model in order to give surgeons superior visual guidance through novel high-dimensional "perspectives" of the surgical area; 4) Hologram-based magnetic navigation improves the accuracy and safety of the screw placement in orthopaedics surgeries; 5) The combination of mixed reality cloud platform and telemedicine system based on 5G provides a new technology platform for telesurgery collaboration. Results of qualitative study encourage the usage of MR technology for orthopaedics surgery. Analysis of the Likert-scale questionnaire shows that MR adds significant value to understanding and communication, spatial awareness, learning and effectiveness. Based on the NASA TLX-scale questionnaire results, mixed reality scored significantly lower under the "mental," "temporal," "performance," and "frustration" categories compared to usual 2D. Conclusion: The integration of MR technology in orthopaedic surgery reduces the dependence on surgeons' experience and provides personalized 3D visualization models for accurate diagnosis and treatment of orthopaedic abnormalities. This integration is clearly one of the prominent future development directions in medical surgery.

m6A hypomethylation of DNMT3B regulated by ALKBH5 promotes intervertebral disc degeneration via E4F1 deficiency.

BACKGROUND: The intervertebral disc (IVD) degeneration is the leading cause of low back pain, which accounts for a main cause of disability. N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNAs and is involved in various diseases and cellular processes by modulating mRNA fate. However, the critical role of m6A regulation in IVD degeneration remains unclear. Nucleus pulposus cell (NPC) senescence is critical for the progression of IVD degeneration. Here, we uncovered the role and explored the regulatory mechanism of m6A in NPC senescence during IVD degeneration. METHODS: Identification of NPC senescence during IVD degeneration was based on the analysis of tissue samples and the cellular model. ALKBH5 upregulation inducing cellular senescence was confirmed by functional experiments in vivo and in vitro. ChIP-qPCR and DNA-Pulldown were used to reveal increased ALKBH5 was regulated by KDM4A-mediated H3K9me3. Furthermore, Me-RIP-seq was performed to identify m6A hypomethylation of DNMT3B transcripts in senescent NPCs. Stability analysis showed that DNMT3B expression was enhanced for less YTHDF2 recognition and increased DNMT3B promoted NPC senescence and IVD degeneration via E4F1 methylation by in vivo and in vitro analyses. RESULTS: Expression of ALKBH5 is enhanced during IVD degeneration and NPC senescence, due to decreased KDM4A-mediated H3K9me3 modification. Functionally, ALKBH5 causes NPC senescence by demethylating DNMT3B transcripts and in turn promoting its expression via less YTHDF2 recognition and following degradation due to transcript hypomethylation in vitro and in vivo. Increased DNMT3B promotes the development of IVD degeneration and NPC senescence, mechanistically by methylating CpG islands of E4F1 at the promoter region and thus restraining its transcription and expression. CONCLUSIONS: Collectively, our findings reveal an epigenetic interplay mechanism in NPC senescence and IVD degeneration, presenting a critical pro-senescence role of ALKBH5 and m6A hypomethylation, highlighting the therapeutic potential of targeting the m6A/DNMT3B/E4F1 axis for treating IVD degeneration.

WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration.

N6-methyladenosine (m6A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m6A regulation in intervertebral disc degeneration (IVDD) remains elusive. Here, we show that methylation of the lncRNA NORAD significantly increases in senescent nucleus pulposus cells (NPCs) by m6A sequencing. Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent NPCs due to an epigenetic increase in H3K4me3 of the promoter mediated by KDM5a, and significantly promotes NORAD m6A modification. Furthermore, YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1/2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. Here, we show interruption of NORAD m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.

Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis.

Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP.

Clinical Outcomes of Uniportal and Biportal Lumbar Endoscopic Unilateral Laminotomy for Bilateral Decompression in Patients with Lumbar Spinal Stenosis: A Retrospective Pair-Matched Case-Control Study.

OBJECTIVE: To compare the clinical outcomes of uniportal and biportal lumbar endoscopic unilateral laminotomy for bilateral decompression (LE-ULBD) in patients with lumbar spinal stenosis. METHODS: A retrospective pair-matched case-control analysis of 72 patients with lumbar spinal stenosis was performed. According to the surgical procedure used, the patients were classified into 2 groups: 1) uniportal LE-ULBD and 2) biportal LE-ULBD. Clinical outcomes were assessed using the visual analog scale score, Oswestry Disability Index score, and Macnab criteria, and the results were compared between the groups. RESULTS: All patients were successfully treated with either uniportal or biportal LE-ULBD. The surgical duration in the biportal LE-ULBD group was significantly shorter than in the uniportal LE-ULBD group (P < 0.001). The time to ambulation and the length of hospitalization in the 2 groups were not significantly different. The visual analog scale and Oswestry Disability Index scores improved significantly after surgery in both groups (P < 0.001). Based on the Macnab criteria, 33 (91.7%) patients in the uniportal LE-ULBD group and 34 (94.4%) patients in the biportal LE-ULBD group were rated as having an excellent or good outcome. Additionally, intraoperative epineurium injury was observed in both the LE-ULBD groups. CONCLUSIONS: Both uniportal and biportal LE-ULBD procedures are safe and effective for treating patients with lumbar spinal stenosis. It is more feasible to decompress the spinal canal during biportal LE-ULBD than during uniportal LE-ULBD.

Comparison of the Clinical Outcomes of Full-Endoscopic Visualized Foraminoplasty and Discectomy Versus Microdiscectomy for Lumbar Disc Herniation.

OBJECTIVE: This retrospective case-control study aimed to evaluate and compare the clinical outcomes of full-endoscopic visualized foraminoplasty and discectomy (FEVFD) with microdiscectomy (MD) for lumbar disc herniation (LDH). METHODS: Data from 198 patients who presented with LDH between January 2016 and December 2017 treated by either FEVFD or MD were retrospectively analyzed. The inclusion criteria were single-level LDH, unilateral radiating leg pain with or without positive Lasegue's sign, and failure of standard conservative treatment for at least 12 weeks. The patients were categorized into an FEVFD group (n = 102) or an MD group (n = 96), according to the surgical procedure performed. Operative time, time in bed after surgery, postoperative hospitalization time, complications, and reoperations were recorded. Visual analog scales (VAS) for leg and back pain, Oswestry Disability index (ODI), 36-Item Short-Form Health Survey physical function (SF36-PF), and bodily pain (SF36-BP) scores were assessed and compared between the two groups. RESULTS: The demographic data and baseline characteristics of the two groups were not significantly different. Operative time for the FEVFD group (73.82 ± 20.73 min) was longer than that for the MD group (64.74 ± 17.37 min) (P = 0.003), and fluoroscopy time for the FEVFD group (1.71 ± 0.58s) was longer than that for the MD group (1.30 ± 0.33s) (P < 0.001). However, time in bed experienced in the FEVFD group (8.51 ± 2.10 h) was less than that in the MD group (9.24 ± 2.01 h) (P = 0.014), and postoperative hospitalization time experienced in the FEVFD group (2.89 ± 0.83d) was also shorter than that in the MD group (4.94 ± 1.35d) (P < 0.001). All patients completed 24 months of follow-up. Postoperative scores at each follow-up for the VAS for leg and back pain, ODI, SF36-PF, and SF36-BP all improved significantly for both groups, as compared to the preoperative data (P < 0.05). The mean preoperative and postoperative scores for the VAS for leg and back pain, ODI, SF36-PF, and SF36-BP were not significantly different between the two groups. According to the modified MacNab criteria, the outcomes of the procedures were rated as excellent or good by 92.16% and 93.75% of the patients in the FEVFD and MD groups, respectively. One patient suffered a nerve root injury during the discectomy, one patient suffered from a dural tear, and two patients suffered from a residual herniation in the FEVFD group. One patient in the MD group suffered from poor wound healing. Moreover, recurrence happened in two cases in the FEVFD group, and in one case in the MD group. CONCLUSION: FEVFD and MD are both reliable techniques for the treatment of symptomatic LDH. FEVFD resulted in a more rapid recovery and equivalent clinical outcomes after 24 months of follow-up.

Biomechanical Evaluation of Different Surgical Approaches for the Treatment of Adjacent Segment Diseases After Primary Anterior Cervical Discectomy and Fusion: A Finite Element Analysis.

Symptomatic adjacent segment disease (ASD) is a common challenge after anterior cervical discectomy and fusion (ACDF). The objective of this study was to compare the biomechanical effects of a second ACDF and laminoplasty for the treatment of ASD after primary ACDF. We developed a finite element (FE) model of the C2-T1 based on computed tomography images. The FE models of revision surgeries of ACDF and laminoplasty were simulated to treat one-level and two-level ASD after primary ACDF. The range of motion (ROM) and intradiscal pressure (IDP) of the adjacent segments, and stress in the cord were analyzed to investigate the biomechanical effects of the second ACDF and laminoplasty. The results indicated that revision surgery of one-level ACDF increased the ROM and IDP at the C2-C3 segment, whereas two-level ACDF significantly increased the ROM and IDP at the C2-C3 and C7-T1 segments. Furthermore, no significant changes in the ROM and IDP of the laminoplasty models were observed. The stress in the cord of the re-laminoplasty model decreased to some extent, which was higher than that of the re-ACDF model. In conclusion, both ACDF and laminoplasty can relieve the high level of stress in the spinal cord caused by ASD after primary ACDF, whereas ACDF can achieve better decompression effect. Revision surgery of the superior ACDF or the superior and inferior ACDF after the primary ACDF increased the ROM and IDP at the adjacent segments, which may be the reason for the high incidence of recurrent ASD after second ACDF.

Corrigendum: Comparison of Clinical Outcomes Following Lumbar Endoscopic Unilateral Laminotomy Bilateral Decompression and Minimally Invasive Transforaminal Lumbar Interbody Fusion for One-Level Lumbar Spinal Stenosis With Degenerative Spondylolisthesis.

[This corrects the article DOI: 10.3389/fsurg.2020.596327.].

Autophagic Degradation of Gasdermin D Protects against Nucleus Pulposus Cell Pyroptosis and Retards Intervertebral Disc Degeneration In Vivo.

Intervertebral disc degeneration (IDD) is the primary culprit of low back pain and renders heavy social burden worldwide. Pyroptosis is a newly discovered form of programmed cell death, which is also involved in nucleus pulposus (NP) cells during IDD progression. Moderate autophagy activity is critical for NP cell survival, but its relationship with pyroptosis remains unknown. This study is aimed at investigating the relationship between autophagy and pyroptotic cell death. The pyroptosis executor N-terminal domain of gasdermin D (GSDMD-N) and inflammation-related proteins were measured in lipopolysaccharide- (LPS-) treated human NP cells. Inhibition of autophagy by siRNA transfection and chemical drugs aggravated human NP cell pyroptosis. Importantly, we found that the autophagy-lysosome pathway and not the proteasome pathway mediated the degradation of GSDMD-N as lysosome dysfunction promoted the accumulation of cytoplasmic GSDMD-N. Besides, P62/SQSTM1 colocalized with GSDMD-N and mediated its degradation. The administration of the caspase-1 inhibitor VX-765 could reduce cell pyroptosis as confirmed in a rat disc IDD model in vivo, whereas ATG5 knockdown significantly accelerated the progression of IDD. In conclusion, our study indicated that autophagy protects against LPS-induced human NP cell pyroptosis via a P62/SQSTM1-mediated degradation mechanism and the inhibition of pyroptosis retards IDD progression in vivo. These findings deepen the understanding of IDD pathogenesis and hold implications in unraveling therapeutic targets for IDD treatment.