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Immune-defensive microspheres promote regeneration of the nucleus pulposus by targeted entrapment of the inflammatory cascade during intervertebral disc degeneration

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Bioactive Materials 2024年第7期37卷 132-152页

作者： Liang Zhou Feng Cai Hongyi Zhu Yichang Xu Jincheng Tang Wei Wang Ziang Li Jie Wu Zhouye Ding Kun Xi Liang Chen Yong Gu Department of Orthopedics Surgery Orthopedic InstituteThe First Affiliated Hospital of Soochow UniversitySoochow University899 Pinghai RoadSuzhouJiangsu215006PR China

Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the *** study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide *** nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting ***@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and ***@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD *** integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.

关键词： Intervertebral disc degeneration nucleus pulposus Hydrogel microsphere Neutrophil membrane Drug release kinetics Cell membrane-coated mimic

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The Artificial Disc nucleus and Other Strategies for Replacement of the nucleus pulposus:Past,Present and Future Designs for an Emerging Surgical Solution

Engineered Regeneration

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Engineered Regeneration 2024年第2期5卷 269-281页

作者： Greg Sacks Vincent DeStefano Claire Parker Ryan Lebens Harry Mushlin Renaissance School of Medicine at Stony Brook University Stony BrookNYUSA

nucleus pulposus(NP)Replacement is a developing surgical methodology for the treatment of pathology related to degeneration of intervertebral discs(IVDs).This article provides necessary context regarding the patholo-gies treated with this technology,the biomechanical structure and function of the IVD,and the procedures this technology aims to ***,it provides an overview and discussion of commercial and experimental preformed and in situ curing prosthesis designs reported in the scientific literature and summarizes the results of biomechanical and clinical studies evaluating their *** and updated information on the most recent research into NP replacement with novel hydrogel and tissue engineering(TE)strategies is *** of the NP allows for potential improvement in the treatment of degenerative spinal pathologies through minimally invasive surgical techniques.

关键词： nucleus pulposus Intradiscal Prosthesis Hydrogel Artificial Disc Implant Spine Surgery

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The role of transcriptional factor brachyury in the development and repair of nucleus pulposus

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BIOCELL 2022年第6期46卷 1363-1364页

作者： YINGHUI WU HONG ZHANG QIANG WANG SUOYUAN LI JUN SHEN Department of Orthopeadic Surgery The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalSuzhou215002China

Transcription factor Brachyury,a protein containing 435 amino acids,has been widely investigated and reported in notochord differentiation and nucleus pulposus *** crucial functions and underlying mechanisms by Brachyury are discussed in this paper,which suggests Brachyury can be developed into a potential novel target for the therapy of intervertebral disc degeneration.

关键词： Brachyury nucleus pulposus Notochord IVD

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Evaluation of CD24 as a marker to rapidly define the mesenchymal stem cell phenotype and its differentiation in human nucleus pulposus

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Chinese Medical Journal 2014年第8期127卷 1474-1481页

作者： Guan Xiaoming Ma Xun Zhang Li Feng Haoyu Ma Zhuo Department of Orthopaedics Surgery Second Hospital Shanxi Medical University Taiyuan Shanxi 030001 China Department of Orthopaedics Surgery Da Yi Hospital Shanxi Medical University Taiyuan Shanxi 030032 China

Background Recent studies have indicated that human nucleus pulposus contain mesenchymal stem cells （NP-MSCs）. However, the immunophenotypic variation of NP-MSCs in vitro was unclear. The present study was conducted to address the immunophenotypic variation of mesenchymal stem cells in nucleus pulposus under continuous proliferation in vitro and show the difference between mesenchymal stem cells and nucleus pulposus cell. Methods Tissue samples were obtained from thoracolumbar burst fracture patients and degenerative disc disease patients who underwent discectomy and fusion procedures. Flow cytometric and laser scanning confocal microscope （LSCM） were used to detect the variation of mesenchymal stem cells in nucleus pulposus which were expressing CD105 and CD24 in condition with or without transforming growth factor [31 （TGF-131）. Results More than 90% of the analyzed primary cells of mesenchymal stem cells in nucleus pulposus fulfilled the general immunophenotyping criteria for MSCs, such as CD44, CD105 and CD29, but the marker of mature NP cells characterized as CD24 was negative. In continuous cultures, the proportion of mesenchymal stem cells which were expressing CD44, CD105 and CD29 in nucleus pulposus gradually decreased. The mesenchymal stem cells in nucleus pulposus cells were positive for CD105 and CD29, with slight positivity for CD44. The CD24 expression gradually increased in proliferation. Bi- parametric flow cytometry and laser scanning confocal microscopy confirmed the presence of cells which were expressing CD105 and CD24 independently, and only a small part of cells expressed both CD105 and CD24 simultaneously. TGF-{31 could stimulate mesenchymal stem cells in nucleus pulposus to express CD24. Conclusions Non-degenerative and degenerative NP contains mesechymal stem cells. The variation of CD24 can be used as a marker to identify the NP-MSCs differentiation into NP-like cells.

关键词： CD24 mesenchymal stem cell nucleus pulposus

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Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2016年第1期17卷 30-42页

作者： Xu-wei LUO Kang LIU Zhu CHEN Ming ZHAO Xiao-wei HAN Yi-guang BAI Gang FENG Research Institute of Tissue Engineering and Stem Cells Nanchong Central Hospital and the Second Clinical Institute of North Sichuan Medical College

Objective： To construct a recombinant adenovirus vector-carrying human growth and differentiation factor-5 （GDF-5） gene, investigate the biological effects of adenovirus-mediated GDF-5 （Ad-GDF-5） on extracellular matrix （ECM） expression in human degenerative disc nucleus pulposus （NP） cells, and explore a candidate gene therapy method for intervertebral disc degeneration （IDD）. Methods： Human NP cells of a degenerative disc were isolated, cultured, and infected with Ad-GDF-5 using the AdEasy-1 adenovirus vector system. On Days 3, 7, 14, and 21, the contents of the sulfated glycosaminoglycan （sGAG）, deoxyribonucleic acid （DNA） and hydroxyproline （Hyp）, synthesis of proteoglycan and collagen II, gene expression of collagen II and aggrecan, and NP cell proliferation were assessed. Results： The adenovirus was an effective vehicle for gene delivery with prolonged expression of GDF-5. Biochemical analysis revealed increased sGAG and Hyp contents in human NP cells infected by Ad-GDF-5 whereas there was no conspicuous change in basal medium （BM） or Ad-green fluorescent protein （GFP） groups. Only cells in the Ad-GDF-5 group promoted the production of ECM, as demonstrated by the secretion of proteoglycan and up-regulation of collagen II and aggrecan at both protein and mRNA levels. The NP cell proliferation was significantly promoted. Conclusions： The data suggest that Ad-GDF-5 gene therapy is a potential treatment for IDD, which restores the functions of degenerative intervertebral disc through enhancing the ECM production of human NP ceils.

关键词： Intervertebral disc Degeneration Growth and differentiation factor-5 (GDF-5) Adenovirus Gene therapy nucleus pulposus

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Autologous nucleus pulposus transplantation to lumbar 5 dorsal root ganglion after epineurium discission in rats： a modified model of non-compressive lumbar herniated intervertebral disc

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Chinese Medical Journal 2011年第13期124卷 2009-2014页

作者： ZHANG Jin-jun SONG Wu LUO Wen-ying WEI Ming SUN Lai-bao ZOU Xue-nong LIAO Wei-ming Department of Anesthesiology/Pain the First Affiliated Hosoital of Sun Yat-Sen UniversityGuangzhou Guangdong 510080 China Department of Gastrointestinal-pancreatic Surgery the First Affiliated Hosoital of Sun Yat-Sen UniversityGuangzhou Guangdong 510080 China D epartment of Orthopaedic Surgery the First Affiliated Hosoital of Sun Yat-Sen UniversityGuangzhou Guangdong 510080 China

Background nucleus pulposus of intervertebral discs has proinflammatory characteristics that play a key role in neuropathic pain in lumbar herniated intervertebral disc. One of the most commonly used animal models （the traditional model） of non-compressive lumbar herniated intervertebral disc is created by L4-L5 hemilaminectomy and the application of autologous nucleus pulposus to cover the left L4 and L5 nerve roots in rats. However, such procedures have the disadvantages of excessive trauma and low success rate. We proposed a modified model of non-compressive lumbar herniated intervertebral disc in which only the left L5 dorsal root ganglion is exposed and transplanted with autologous nucleus pulposus following incision of epineurium. We aimed to compare the modified model with the traditional one with regard to trauma and success rate. Methods Thirty Sprague-Dawley male rats were randomized into three groups： sham operation group （n=6）, traditional group （n=12）, and modified group （n=12）. The amount of blood loss and operative time for each group were analyzed. The paw withdrawal threshold of the left hind limb to mechanical stimuli and paw withdrawal latency to heat stimuli were examined from the day before surgery to day 35 after surgery. Results Compared with the traditional group, the modified group had shorter operative time, smaller amount of blood loss, and higher success rate （91.7% versus 58.3%, P 〈0.05）. There was no decrease in paw withdrawal latency in any group. The sham operation group had no decrease in postoperative paw withdrawal threshold, whereas the modified and traditional groups had significant reduction in paw withdrawal threshold after surgery （mechanical hyperalgesia）. Conclusions Transplantation of nucleus pulposus onto the L5 dorsal root ganglion following incision of epineurium in rats established an improved animal model of non-compressive lumbar herniated intervertebral disc with less trauma and more stable pain ethology.

关键词： lumbar herniated intervertebral disc nucleus pulposus hyperalgesia rat animal model

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Effects of degenerative autologous nucleus pulposus on the lumbar sympathetic trunk: Sympathetic inflammation in rats

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Translational Neuroscience and Clinics 2017年第4期3卷 213-219页

作者： Yuanzhang Tang Jingjing Bian Yuna Guo Chenli Sun Yawei Xiuhua Li Jiaxiang Ni Department of Pain Management Xuanwu HospitalCapital Medical University Department of Anesthesiology Yuquan HospitalMedical CenterTsinghua University

Objective: We have reported the presence of discogenic visceral pain secondary to anterior herniation of the lumbar disc. The aim of this study was to observe the inflammatory response of the sympathetic trunk to an autologous degenerative nucleus pulposus(NP) injection under fluoroscopy. Methods: A total of 72 rats were used. In 24 rats,the autologous NP suspension was injected into the right sympathetic trunk. Next,food intake and body weight of each rat were monitored for 14 days. Fourteen days after the injection,the right lumbar sympathetic trunk was harvested for histological assessment,and protein levels of IL-1 β,IL-6,and TNF-α were quantified via ELISA. Results: In the NP-treated group,endoneural hyperemia and intensive infiltration of inflammatory cells could be identified in sections of the sympathetic trunk by the hematoxylin and eosin(H&E) stain. Meanwhile,elevated concentrations of IL-1 β,IL-6,and TNF-α were determined in the sympathetic trunk of the NP group as compared to that of the na?ve and control groups,which indicated the development of an inflammatory response. Furthermore,food intake and body weight of rats in the NP group decreased significantly. Conclusions: The results indicated that an inflammatory response in the sympathetic trunk can be caused by anterior herniation of the lumbar disc,which can generate a sympathetic inflammatory pain response.

关键词： sympathetic trunk nucleus pulposus inflammation lumbar spine disc herniation

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TIGAR mediates the inhibitory role of hypoxia on ROS production and apoptosis in rat nucleus pulposus cells

TIGAR mediates the inhibitory role of hypoxia on ROS product...

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第二十四届中国中西医结合骨伤科学术年会

作者： Li-Bo Jiang Hui-Ren Wang Xi-Lei Li Jian Dong Department of Orthopedic Surgery Zhongshan Hospital Fudan University

Objective Hypoxia has been shown to inhibit reactive oxygen species(ROS)production in nucleus pulposus(NP)*** TP53-induced glycolysis and apoptosis regulator(TIGAR)has been reported to suppress oxidative *** sought to explore the role of TIGAR in the effect of hypoxia on ROS production and *** An intervertebral disc degeneration(IDD)model of Sprague-Dawley(SD)rat caudal spine was established by stabbing their intervertebral *** expression was detected by immunohistochemistry in human and SD rat NP tissues of degenerated *** primary NP cells treated with hypoxia and cobalt chloride(CoCl)were analyzed by western blotting for TIGAR *** TIGAR inhibition with TIGAR siRNA transfection,apoptosis percentage,mitochondrial and total intracellular ROS levels were *** was used to further check the effects of TIGAR on oxidative ***,NADPH/NADPand GSH/GSSH ratio were examined after TIGAR silencing under hypoxic conditions and after HO *** degree-dependent increase in TIGAR expression was observed in human and rat degenerated NP *** and hypoxia-inducer CoClenhanced TIGAR and P53 expressions in rat NP *** inhibition reversed the inhibitory effects of hypoxia on intracellular and mitochondrial ROS production,as well as apoptosis ***,TIGAR inhibition aggravated HO-induced ROS *** addition,TIGAR increased NADPH/NADPand GSH/GSSH ratio in NP *** hese results suggested that TIGAR appears to mediate the protective role of hypoxia on ROS production and apoptosis percentage by enhancing NADPH/NADP+and GSH/GSSH ratio.

关键词： ntervertebral disc degeneration nucleus pulposus Hypoxia Reactive oxygen species TP53-induced glycolysis and apoptosis regulator

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Effect of electroacupuncture on E-prostanoid 2 expression in the spinal cord in rats with neuropathic pain

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Journal of Traditional Chinese Medicine 2017年第4期37卷 496-502页

作者： Ji Lili Jiang Huili Ren Xiujun Guo Mengwei Ge Dongyu Li Genmao Tu Ya School of Acupuncture-moxibustion and Tuina Beijing University of Chinese Medicine Beijing 100029 China School of Basic Medicine Beijing University of Chinese Medicine Beijing 100029 China

OBJECTIVE: To observe the effect of electroacupuncture(EA) treatment on the expression of E-prostanoid 2(EP2) in the spinal cord using a rat model of neuropathic pain, and to examine the effect of different acupuncture ***: Rats were randomly divided into six groups: a normal group, model group, sham group,EA 1 group(distal-proximal acupoints), EA 2 group(proximal acupoints), and EA 3 group(distal acupoints). Rats in the EA groups were treated for20 min, once daily for 7 days. The mechanical withdrawal threshold was evaluated at 1 day preoperatively and at 3, 5, and 7 days postoperatively. At 7days postoperatively, hematoxylin-eosin(HE) staining was used to investigate spinal morphological changes. Spinal EP2 messenger ribonucleic acid(m RNA) was detected using reverse-transcription polymerase chain ***: After the EA treatment, the mechanical withdrawal threshold was up-regulated compared with the model group(P 0.05). The EA 1and EA 2 groups showed a larger treatment effect than the EA 3 group. The HE results showed that EA can improve spinal histomorphology induced by neuropathic ***: EA had a strong analgesic and anti-inflammatory effect. The therapeutic effect of EA on the down-regulation of spinal EP2 m RNA expression may be greater when either local acupoints or a distal-proximal combination of acupoints are used than when distal points are used.

关键词： Neuropathic pain Electroacupuncture nucleus pulposus E-prostanoid 2 Spinal cord

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Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2269-2280页

作者： Yun Teng Yixue Huang Hao Yu Cenhao Wu Qi Yan Yingjie Wang Ming Yang Haifeng Xie Tianyi Wu Huilin Yang Jun Zou Department of Orthopaedic Surgery the First Affiliated Hospital of Soochow UniversitySuzhou 215006China

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

关键词： Nimbolide SIRT1 Intervertebral disc degeneration nucleus pulposus Macrophage polarization Cholesterol

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