Biomimetic bone-periosteum scaffold for spatiotemporal regulated innervated bone regeneration and therapy of osteosarcoma.

The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca2+ and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Molecular mechanism and therapeutic potential of HDAC9 in intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression. METHODS: The contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells. RESULTS: HDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability. CONCLUSION: Our results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.

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.

Improvement of Pulmonary Function and Reconstructed 3-Dimensional Lung Volume After Halo-Pelvic Traction Combined With Posterior Correction for Severe Rigid Spinal Scoliosis: A Multicenter Study.

BACKGROUND AND OBJECTIVES: Severe rigid spinal scoliosis (SRSS) leads to severe restrictive ventilation dysfunction. Currently, the reports about the influence of preoperative halo-pelvic traction (HPT) combined with correction surgery on pulmonary function in patients with SRSS were relatively few. This study aims to investigate (1) the influence of preoperative HPT on lung volume and pulmonary function, (2) the further influence of the following correction surgery on lung volume and pulmonary function, and (3) the relationship among deformity correction, pulmonary function test outcomes, and computed tomography-based lung volume. METHODS: A total of 135 patients with SRSS who underwent preoperative HPT and followed low-grade osteotomy correction surgery were reviewed. Spinal parameters, including proximal thoracic curve, main thoracic curve (MTC), lumbar curve, coronal balance, thoracic kyphosis, lumbar lordosis, sagittal vertical axis, pulmonary function test outcomes (forced vital capacity [FVC], the percentage of predicted forced vital capacity [FVC%], forced expiratory volume in 1 second [FEV1], total lung capacity [TLC]), and lung volume (Vin), were analyzed before, after HPT and at the final follow-up, respectively. RESULTS: The mean FVC, FVC%, FEV1, and TLC increased from 1.67 L, 51.13%, 1.47 L, and 2.37 L to 1.95 L, 64.35%, 1.75 L, and 2.78 L, respectively, after HPT and further improved to 2.22 L, 72.14%, 1.95 L, and 3.15 L, respectively, at the final follow-up. The mean Vin increased from 1.98 L to 2.42 L after traction and further increased to 2.76 L at the final follow-up. The variation of MTC was correlated with the improvement of FVC (r = 0.429, P = .026), FVC% (r = 0.401, P = .038), FEV1 (r = 0.340, P = .043), and TLC (r = 0.421, P = .029) and the variation of Vin (r = 0.425, P = .015) before HPT and after surgery. CONCLUSION: Preoperative HPT can improve preoperative pulmonary function and enhance the preoperative lung volume. There were significant correlations among the variations of MTC, pulmonary function indexes, and lung volume before HPT and after surgery in patients with SRSS.

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.

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration.

BACKGROUND: Extracellular matrix stiffness is emerging as a crucial mechanical cue that drives the progression of various diseases, such as cancer, fibrosis, and inflammation. The matrix stiffness of the nucleus pulposus (NP) tissues increase gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In addition, mitochondrial dynamics play a key role in various cellular functions. An in-depth investigation of the pathogenesis of IDD can provide new insights for the development of effective therapies. In this study, we aim to investigate the effects of matrix stiffness on mitochondrial dynamics in IDD. METHODS: To build the gradient stiffness model, NP cells were cultured on polystyrene plates with different stiffness. Western blot analysis, and immunofluorescence staining were used to detect the expression of mitochondrial dynamics-related proteins. Flow cytometry was used to detect the mitochondrial membrane potential and intracellular Ca2+ levels. Apoptosis related proteins, ROS level, and TUNEL staining were performed to assess the effect of substrate stiffness on NP cells. RESULTS: Stiff substrate increased phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 by activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which promoted mitochondrial fission and apoptosis in NP cells. Furthermore, Piezo1 activation was involved in the regulation of the post-translational modifications of Drp1 and mitochondrial fission caused by matrix stiffness. Inhibition of Piezo1 and ERK1/2 can effectively reduce stiffness-induced ROS elevation and apoptosis in NP cells. CONCLUSIONS: Our results revealed that stiff substrate causes Piezo1 activation and Ca2+ influx, results in ERK1/2 activation and phosphorylation of Drp1 at S616, and finally leads to mitochondrial fission and apoptosis in NP cells. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for treating IDD.

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.

Sonodynamic amplification of cGAS-STING activation by cobalt-based nanoagonist against bone and metastatic tumor.

The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by 'cold' tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in 'cold' tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.

The contribution of preoperative balanced halo-pelvic traction to severe rigid spinal deformity correction.

PURPOSE: The aim of this study was to assess the clinical efficacy of balanced halo-pelvic traction (HPT) and evaluate its contribution to the correction surgery in treating adult severe rigid spinal deformity. METHODS: One hundred and eight adult patients with severe rigid spinal deformity who underwent preoperative HPT and correction surgery were reviewed. The main coronal curve, segmental kyphotic angle, coronal balance (CB), sagittal balance (SVA), and the length of spine were measured before HPT, after HPT, post-operatively, and at final follow-up. The HPT contribution rates to deformity correction were calculated. RESULTS: The pre-HPT main coronal curve was 103.4 ± 10.6°, improved to 61.0 ± 13.4° after traction and further improved to 44.2 ± 10.2° after surgical correction, and maintained at 50.3 ± 9.9° at final follow-up. CB started at 4.2 ± 4.8 cm, improved to 2.1 ± 2.5 cm after HPT, 0.8 ± 1.2 cm after operation, and 0.7 ± 0.9 cm at final follow-up. The pre-HPT sagittal segmental kyphotic angle was 67.3 ± 17.7°, was then improved to 42.2 ± 27.5° after traction and further improved to 34.9 ± 10.2° after surgery, and maintained at 35.4 ± 10.4° at final follow-up. The length of spine improved from 35.9 ± 5.9 to 42.6 ± 6.0 cm via HPT, reached up to 45.0 ± 6.0 cm after operation, and maintained at 44.3 ± 5.2 cm at final follow-up. CONCLUSION: HPT is effective for the treatment of severe rigid spinal deformity. Balanced HPT can dramatically improve coronal and sagittal deformity as well as spinal length before corrective surgery.

Biomechanical Comparison of Different Surgical Approaches for the Treatment of Adjacent Segment Diseases after Primary Transforaminal Lumbar Interbody Fusion: A Finite Element Analysis.

BACKGROUND AND OBJECTIVE: Adjacent segment disease (ASD) is a well-known complication after interbody fusion. Revision surgery is necessary for symptomatic ASD to further decompress and fix the affected segment. However, no optimal construct is accepted as a standard in treating ASD. The purpose of this study was to compare the biomechanical effects of different surgical approaches for the treatment of ASD after primary transforaminal lumbar interbody fusion (TLIF). METHODS: A finite element model of the L1-S1 was conducted based on computed tomography scan images. The primary surgery model was developed with a single-level TLIF at L4-L5 segment. The revision surgical models were developed with anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), or TLIF at L3-L4 segment. The range of motion (ROM), intradiscal pressure (IDP), and the stress in cages were compared to investigate the biomechanical influences of different surgical approaches. RESULTS: The results indicated that all the three surgical approaches can stabilize the spinal segment by reducing the ROM at revision level. The ROM and IDP at adjacent segments of revision model of TLIF was greater than those of other revision models. While revision surgery with ALIF and LLIF had similar effects on the ROM and IDP of adjacent segments. Compared among all the surgical models, cage stress in revision model of TLIF was the maximum in extension and axial rotation. CONCLUSION: The IDP at adjacent segments and stress in cages of revision model of TLIF was greater than those of ALIF and LLIF. This may be that direct extension of the surgical segment in the same direction results in stress concentration.

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.

A controllable perfusion microfluidic chip for facilitating the development of retinal ganglion cells in human retinal organoids.

Retinal organoids (ROs) derived from human pluripotent stem cells (hPSCs) have become a promising model in vitro to recapitulate human retinal development, which can be further employed to explore the mechanisms of retinal diseases. However, the current culture systems for ROs lack physiologically relevant microenvironments, such as controllable mechano-physiological cues and dynamic feedback between cells and the extracellular matrix (ECM), which limits the accurate control of RO development. Therefore, we designed a controllable perfusion microfluidic chip (CPMC) with the advantages of precisely controlling fluidic shear stress (FSS) and oxygen concentration distribution in a human embryonic stem cell (hESC)-derived RO culture system. We found that ROs cultured under this system allow for expanding the retinal progenitor cell (RPC) pool, orchestrating the retinal ganglion cell (RGC) specification, and axon growth without disturbing the spatial and temporal patterning events at the early stage of RO development. Furthermore, RNA sequencing data revealed that the activation of voltage-gated ion channels and the increased expression of ECM components synergistically improve the growth of ROs and facilitate the differentiation of RGCs. This study elaborates on the advantages of the designed CPMC to promote RO growth and provide a controllable and reliable platform for the efficient maturity of RGCs in the ROs, promising applications in modeling RGC-related disorders, drug screening, and cell transplantation.

Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification.

Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (DIX) domain-containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with disrupted in schizophrenia 1 (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.

The role of extracellular vesicles in iron homeostasis and ferroptosis: Focus on musculoskeletal diseases.

Iron homeostasis is crucial for maintaining proper cellular function, and its disruption is considered one of the pathogenic mechanisms underlying musculoskeletal diseases. Under conditions of oxidative stress, the accumulation of cellular iron overload and lipid peroxidation can lead to ferroptosis. Extracellular vesicles (EVs), serving as mediators in the cell-to-cell communication, play an important role in regulating the outcome of cell ferroptosis. Growing evidence has proven that EV biogenesis and secretion are tightly associated with cellular iron export. Furthermore, different sources of EVs deliver diverse cargoes to bring about phenotypic changes in the recipient cells, either activating or inhibiting ferroptosis. Thus, delivering therapies targeting ferroptosis through EVs may hold significant potential for treating musculoskeletal diseases. This review aims to summarize current knowledge on the role of EVs in iron homeostasis and ferroptosis, as well as their therapeutic applications in musculoskeletal diseases, and thereby provide valuable insights for both research and clinical practice.

Improvement of pulmonary function and reconstructed 3D lung volume after deformity correction for thoracic spinal posttubercular kyphosis: a multicenter study.

OBJECTIVE: The aim of this study was to investigate the influence of corrective surgery on thoracic spinal posttubercular kyphosis (PTK) with respect to lung volume and pulmonary function. METHODS: This was a retrospective study of 126 patients (72 males and 54 females) who underwent posterior vertebral column resection (PVCR) for severe thoracic spinal PTK between September 2013 and June 2020. The patients' spinal parameters, results of their pulmonary function test (PFT), and CT-based 3D lung volume were recorded and analyzed preoperatively and at final follow-up. The correlation of kyphosis correction with the PFT and lung volume was evaluated. RESULTS: The mean local kyphosis decreased from 112.5° to 37.2°, and the mean local scoliosis decreased from 20.9° to 5.2°; C2-7 lordosis, thoracic kyphosis, and lumbar lordosis also significantly improved after surgery. The mean CT-based lung volume significantly increased from 2.9 L preoperatively to 3.6 L at the final follow-up. The indices of PFT, including forced vital capacity (FVC), percent predicted FVC, total lung capacity, and forced expiratory volume in 1 second, were also significantly improved, and 60 patients with pulmonary dysfunction recovered to normal at the final follow-up. The correlation analysis revealed that the correction of local kyphosis was closely correlated with the improvement in PFT and the increase in lung volume. CONCLUSIONS: PVCR cannot only effectively realign the spine in patients with severe thoracic spinal PTK deformity but also significantly improve pulmonary function. Adequate local kyphosis correction should be highly valued, as it is a key factor in increasing lung volume.

Global realignment after posterior vertebral column resection in severe thoracolumbar post-tubercular kyphosis: correlation with patient-reported outcomes.

PURPOSE: To investigate spinal realignment in patients with severe post-tubercular kyphosis (PTK) who underwent posterior vertebral column resection (PVCR) and its correlation with patient-reported outcomes (PROs). METHODS: Eighty-two patients were included in this study. Spinopelvic parameters (focal scoliosis (FS), coronal balance (CB), sagittal vertical axis (SVA), focal kyphosis (FK), C2-7 lordosis (CL), thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), and pelvic incidence minus lumbar lordosis (PI-LL)) and PROs (Visual Analog Scale (VAS) and Oswestry Disability Index (ODI)) were analyzed. The correlation between spinopelvic parameters and PROs was evaluated. RESULTS: FK, FS, CL, TK, LL, and PI-LL significantly changed after surgery. FK decreased from pre-operative 108.5 ± 16.4° to 31.8 ± 4.5° at three months after surgery and increased to 38.7 ± 6.6° at final follow-up (P < 0.001). FS decreased from pre-operative 20.9 ± 2.2° to 5.1 ± 2.2° at final follow-up (P < 0.001). CL decreased from pre-operative 7.2 ± 7.3° to 3.3 ± 8.3° at final follow-up (P = 0.002). TK improved from pre-operative - 5.6 ± 7.1° to 12.9 ± 8.2° at final follow-up (P < 0.001). LL decreased from pre-operative 75.5 ± 12.6° to 45.5 ± 7.9° at final follow-up (P < 0.001). PI-LL improved from pre-operative - 24.8 ± 13.4° to 4.8 ± 9.9° at final follow-up (P < 0.001). The improvement of PROs was found to be significantly correlated with the variations of FK, CL, TK, LL, and PI-LL. The multiple regression analysis revealed that FK was an independent predictor for the improvement of VAS and ODI. CONCLUSIONS: PVCR is effective in treating severe PTK, which can significantly improve patients' clinical and radiographic outcomes. Spine surgeons should pay more attention to reducing the residual kyphosis.

Total en bloc spondylectomy of thoracic giant cell tumor with secondary aneurysmal bone cyst: case reports and review of literature.

Spinal giant cell tumor (GCT) combined with secondary aneurysmal bone cyst (ABC) is a locally aggressive primary bone tumor. Total en bloc spondylectomy has never been reported to treat thoracic GCT combined with secondary ABC. We retrospectively reviewed two cases of spinal GCT combined with secondary ABC. A 41-year-old male patient was presented with back pain due to irregular expansive bone destruction involving the T6 vertebral body and intraspinal space-occupying lesion. Total en bloc spondylectomy of T6 vertebra was performed with good neurological status after the surgery. A 29-year-old female patient was presented with right scapular region pain due to irregular expansive bone destruction involving the T5 vertebral body and intraspinal space-occupying lesion. Total en bloc spondylectomy of T5 vertebra was performed with good neurological status after the surgery. Adjuvant radiation therapy was applied after the surgery without local recurrence at the 12-month or 24-month follow-up. Spinal GCT combined with secondary ABC appears to have a high local recurrence rate. Therefore, total en bloc spondylectomy should be applied to treat thoracic GCT combined with secondary ABC.

Case Report: Transvertebral transposition of the spinal cord for recovery after paraplegia during kyphoscoliosis surgery.

Introduction: Neurological impairment during spinal deformity surgery is the most serious possible complication. When confronting intraoperative neurophysiological monitoring alerts, various surgical management methods such as the release of implants and decompression of the spinal cord are always performed. Transvertebral transposition of the spinal cord is rarely performed, and its role in the management of acute paraplegia is seldom reported. Case description: The authors present two patients with kyphoscoliosis who experienced neurological deficits and abnormal neurological monitoring intraoperatively or post-operatively that were detected during correction surgery. Acute paraplegia was confirmed by a wake-up test. Subsequent spinal cord transposition was performed. Intraoperative neurophysiological monitoring motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs) were performed to detect the changes during the process. After transvertebral transposition of the spinal cord, the MEPs and SEPs were significantly improved in both patients during surgery. The spinal cord function was restored post-operatively and recovered to normal at the final follow-up in two patients. Conclusion: This case demonstrated that instead of decreasing the correction ratio of kyphoscoliosis, transvertebral transposition of the spinal cord under intraoperative neurophysiological monitoring may be an alternative therapeutic strategy for acute spinal cord dysfunction caused by deformity correction surgeries.

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.