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Fibroadhesive scarring of grafted collagen scaffolds interferes with implant–host neural tissue integration and bridging in experimental spinal cord injury

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Regenerative Biomaterials 2019年第2期6卷 75-87页

作者： Haktan Altinova Sebastian Hammes Moniek Palm Jose Gerardo-Nava Pascal Achenbach Ronald Deumens Emmanuel Hermans Tobias Fuhrmann Arne Boecker Sabien Geraldine Antonia van Neerven Ahmet Bozkurt Joachim Weis Gary Anthony Brook Department of Neurosurgery RWTH Aachen University HospitalAachenGermany Institute of Neuropathology RWTH Aachen University HospitalAachenGermany Police Headquarters Berlin Medical CommissionBerlinGermany Institute of Neuroscience Universite Catholique de LouvainBrusselsBelgium Donnelly Centre for Cellular&Biomolecular Research University of TorontoTorontoCanada Department of Hand- Plastic and Reconstructive SurgeryBurn Centre Trauma CentreBG Trauma Centre LudwigshafenUniversity of HeidelbergLudwigshafenGermany Department of Plastic Reconstructive and Hand SurgeryBurn CentreRWTH Aachen University HospitalAachenGermany Department of Plastic AestheticHand and Burn SurgeryHelios University Hospital WuppertalUniversity Witten/HerdeckeWuppertalGermany

Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable *** is generally accepted that future intervention strategies will require combinational approaches,including bioengineered scaffolds,to support axon growth across tissue scarring and cystic ***,we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue ***,we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal *** demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells,the fine processes of which extended along the graft–host *** reactive astroglial or regenerating axonal profiles could be seen traversing this *** encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the *** of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.

关键词： spinal cord injury CNS-scarring type-I collagen scaffold astrogliosis fibrosis encapsulation

Huangqin flavonoid extraction for spinal cord injury in a rat model

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Neural Regeneration Research 2018年第12期13卷 2200-2208页

作者： Qian Zhang Li-Xin Zhang Jing An Liang Yan Cui-Cui Liu Jing-Jing Zhao Hao Yang Translational Medicine Center Hong Hui Hospital Xi'an Jiaotong University Department of Clinical Pharmacy Hong Hui Hospital Xi'an Jiaotong University Department of Spine Surgery Hong Hui Hospital Xi'an Jiaotong University

Flavonoids from Huangqin（dried roots of Scutellaria baicalensis Georgi） have anti-inflammatory effects, and are considered useful for treatment of spinal cord injury. To verify this hypothesis, the T9-10 spinal cord segments of rats were damaged using Allen＇s method to establish a rat spinal cord injury model. Before model establishment, Huangqin flavonoid extraction（12.5 g/kg） was administered intragastrically for 1 week until 28 days after model establishment. Methylprednisolone（30 mg/kg） was injected into the tail vein at 30 minutes after model establishment as a positive control. Basso, Beattie, and Bresnahan locomotor scale scores were used to assess hind limb motor function. Hematoxylin-eosin staining was used to detect pathological changes in the injured spinal cord. Immunofluorescence and western blot assays were performed to measure immunoreactivity and expression levels of brain-derived neurotrophic factor, neuronal marker neurofilament protein, microglial marker CD11 b and astrocyte marker glial fibrillary acidic protein in the injured spinal cord. Huangqin flavonoid extraction markedly reduced spinal cord hematoma, inflammatory cell infiltration and cavities and scars, and increased the Basso, Beattie, and Bresnahan locomotor scale scores; these effects were identical to those of methylprednisolone. Huangqin flavonoid extraction also increased immunoreactivity and expression levels of brain-derived neurotrophic factor and neurofilament protein, and reduced immunoreactivity and expression levels of CD11 b and glial fibrillary acidic protein, in the injured spinal cord. Overall, these data suggest that Huangqin flavonoid extraction can promote recovery of spinal cord injury by inducing brain-derived neurotrophic factor and neurofilament protein expression, reducing microglia activation and regulating reactive astrocytes.

关键词： nerve regeneration spinal cord injury flavonoids Scutellaria baicalensis neurofilament brain-derived neurotrophic factor astrocytes rnicroglia neural regeneration

VX-765 reduces neuroinflammation after spinal cord injury in mice

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Neural Regeneration Research 2021年第9期16卷 1836-1847页

作者： Jing Chen Yu-Qing Chen Yu-Jiao Shi Shu-Qin Ding Lin Shen Rui Wang Qi-Yi Wang Cheng Zha Hai Ding Jian-Guo Hu He-Zuo Lü Clinical Laboratory the First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhui ProvinceChina Anhui Key Laboratory of Tissue Transplantation the First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhui ProvinceChina Department of Immunology Bengbu Medical Collegeand Anhui Key Laboratory of Infection and Immunity at Bengbu Medical CollegeBengbuAnhui ProvinceChina

Inflammation is a major cause of neuronal injury after spinal cord injury. We hypothesized that inhibiting caspase-1 activation may reduce neuroinflammation after spinal cord injury, thus producing a protective effect in the injured spinal cord. A mouse model of T9 contusive spinal cord injury was established using an Infinite Horizon Impactor, and VX-765, a selective inhibitor of caspase-1, was administered for 7 successive days after spinal cord injury. The results showed that:(1) VX-765 inhibited spinal cord injury-induced caspase-1 activation and interleukin-1β and interleukin-18 secretion.(2) After spinal cord injury, an increase in M1 cells mainly came from local microglia rather than infiltrating macrophages.(3) Pro-inflammatory Th1 Th17 cells were predominant in the Th subsets. VX-765 suppressed total macrophage infiltration, M1 macrophages/microglia, Th1 and Th1 Th17 subset differentiation, and cytotoxic T cells activation;increased M2 microglia;and promoted Th2 and Treg differentiation.(4) VX-765 reduced the fibrotic area, promoted white matter myelination, alleviated motor neuron injury, and improved functional recovery. These findings suggest that VX-765 can reduce neuroinflammation and improve nerve function recovery after spinal cord injury by inhibiting caspase-1/interleukin-1β/interleukin-18. This may be a potential strategy for treating spinal cord injury. This study was approved by the Animal Care Ethics Committee of Bengbu Medical College(approval No. 2017-037) on February 23, 2017.

关键词： immune cell subsets immune function inflammasomes leukocyte infiltration macrophages microglia pathways spinal cord injury

Safety and effectiveness of electromyography-induced rehabilitation treatment after epidural electrical stimulation for spinal cord injury:study protocol for a prospective,randomized,controlled trial

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Neural Regeneration Research 2023年第4期18卷 819-824页

作者： Xiao-Pei Sun Jie-Jian Shi Yong Bao Jie Zhang Hui-Juan Pan Dian-You Li Yu Liang Qing Xie Ruijin Hospital Shanghai Jiao Tong University School of MedicineShanghaiChina Shanghai Ruijin Rehabilitation Hospital ShanghaiChina

Epidural electrical stimulation is a new treatment method for spinal cord injury(SCI).Its efficacy and safety have previously been *** treatment after epidural electrical stimulation is important to ensure and improve the postoperative efficacy of epidural electrical stimulation in patients with *** that electromyography(EMG)-induced rehabilitation treatment can accurately match the muscle contraction of patients with SCI,we designed a study protocol for a prospective,randomized controlled *** this trial,on the premise of adjusting the spinal cord electrical stimulator to obtain the maximum EMG signal of the target muscle,patients with SCI receiving epidural electrical stimulation will undergo EMG-induced rehabilitation *** of muscle strength of key muscles,quality of life,safety and therapeutic effects will be *** patients with SCI who are scheduled to undergo epidural electrical stimulation in Shanghai Ruijin Rehabilitation Hospital will be randomly divided into two groups with 10 patients per *** control group will receive conventional rehabilitation *** EMG-induced rehabilitation group will receive EMG-induced rehabilitation treatment of the target muscles of the upper and lower limbs based on conventional rehabilitation *** rehabilitation treatment,follow up for all patients will occur at 2 weeks and 1,3 and 6 *** primary outcome measure of this trial will be evaluation of target muscle recovery using the Manual Muscle Testing grading *** outcome measures will include modified Barthel Index scores,integrated EMG values,the visual analogue scale,spinal cord Independence Measure scores,and modified Ashworth scale *** safety indicator will be the incidence of adverse *** trial will collect data regarding the therapeutic effects of EMG-induced rehabilitation in patients with SCI receiving epidural electrical stimulation for 6 months after r

关键词： electromyography-induced rehabilitation epidural electrical stimulation muscle strength pain quality of life randomized controlled trial recovery spinal cord injury

Ruxolitinib improves the inflammatory microenvironment,restores glutamate homeostasis,and promotes functional recovery after spinal cord injury

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Neural Regeneration Research 2024年第11期19卷 2499-2512页

作者： Jiang Cao Xiao Yu Jingcheng Liu Jiaju Fu Binyu Wang Chaoqin Wu Sheng Zhang Hongtao Chen Zi Wang Yinyang Xu Tao Sui Jie Chang Xiaojian Cao Department of Orthopedics The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina Department of Trauma Surgery Subei People’s Hospital of JiangsuClinical Medical College of Yangzhou UniversityYangzhouJiangsu ProvinceChina Department of Orthopedics Zhongda HospitalSoutheast UniversityNanjingJiangsu ProvinceChina Department of Orthopedic Surgery Nanjing Drum Tower HospitalThe Affiliated Hospital of Medical School of Nanjing UniversityNanjingJiangsu ProvinceChina

The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord ***,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine *** studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains *** address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord *** sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory ***,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic ***,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.

关键词： astrocytes EAAT2 excitotoxicity glutamate homeostasis JAK-STAT pathway locomotor function neurotoxicity ruxolitinib spinal cord injury transcriptome analysis

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury

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Neural Regeneration Research 2020年第10期15卷 1912-1919页

作者： Bo-Tao Tan Hui Jiang Aaron JMoulson Xiao-Liang Wu Wen-Chun Wang Jie Liu Ward TPlunet Wolfram Tetzlaff Department of Rehabilitation Medicine The Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina International Collaboration on Repair Discoveries(Icord) Blusson Spinal Cord CenterVancouverBritish ColumbiaCanada Department of Zoology University of British ColumbiaVancouverBritish ColumbiaCanada Department of spinal Surgery Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Rehabilitation Medicine The General Hospital of Western Theater Command PLAChengduSichuan ProvinceChina

We have previously shown that induction of ketosis by ketogenic diet(KD)conveyed neuroprotection following spinal cord injury in rodent models,however,clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury *** we investigated the use of exogenous ketone supplementation(ketone sodium,KS)combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult *** uninjured rats,ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord ***,ketone levels in KD+KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD *** still demonstrated neuroprotective effects of KD+KS treatment that extend our previous neuroprotective observations with KD *** results showed increased neuronal and axonal sparing in the dorsal corticospinal ***,better performance of forelimb motor abilities were observed on the Montoya staircase(for testing food pellets reaching)at 4 and 6 weeks post-injury and rearing in a cylinder(for testing forelimb usage)at 6 and 8 weeks *** together,the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following *** salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function *** study was approved by the Animal Care Committee of the University of British Columbia(protocol No.A14-350)on August 31,2015.

关键词： axon behavior corticospinal tract ketogenic diet ketone supplementation myelin neuroprotection spinal cord injury

Early electrical field stimulation prevents the loss of spinal cord anterior horn motoneurons and muscle atrophy following spinal cord injury

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Neural Regeneration Research 2018年第5期13卷 869-876页

作者： Cheng Zhang Wei Rong Guang-Hao Zhang Ai-Hua Wang Chang-Zhe Wu Xiao-Lin Huo Beijing Key Laboratory of Bioelectromagnetism Institute of Electrical Engineering Chinese Academy of Sciences Beijing China Department of Orthopedics Beijing Tsinghua Changgung Hospital Medical Center Tsinghua University Beijing China University of Chinese Academy of Sciences Beijing China

Our previous study revealed that early application of electrical field stimulation（EFS） with the anode at the lesion and the cathode distal to the lesion reduced injury potential, inhibited secondary injury and was neuroprotective in the dorsal corticospinal tract after spinal cord injury（SCI）. The objective of this study was to further evaluate the effect of EFS on protection of anterior horn motoneurons and their target musculature after SCI and its mechanism. Rats were randomized into three equal groups. The EFS group received EFS for 30 minutes immediately after injury at T_（10）. SCI group rats were only subjected to SCI and sham group rats were only subjected to laminectomy. Luxol fast blue staining demonstrated that spinal cord tissue in the injury center was better protected; cross-sectional area and perimeter of injured tissue were significantly smaller in the EFS group than in the SCI group. Immunofluorescence and transmission electron microscopy showed that the number of spinal cord anterior horn motoneurons was greater and the number of abnormal neurons reduced in the EFS group compared with the SCI group. Wet weight and cross-sectional area of vastus lateralis muscles were smaller in the SCI group to in the sham group. However, EFS improved muscle atrophy and behavioral examination showed that EFS significantly increased the angle in the inclined plane test and Tarlov＇s motor grading score. The above results confirm that early EFS can effectively impede spinal cord anterior horn motoneuron loss, promote motor function recovery and reduce muscle atrophy in rats after SCI.

关键词： nerve regeneration spinal cord injury electrical field stimulation anterior horn motoneurons vastus lateralis muscle Tarlov's motor grading scale inclined plane test choline acetyltransferase transmission electron microscopy neural regeneration

Transplantation of Nogo-66 receptor gene-silenced cells in a poly(D,L-lactic-co-glycolic acid) scaffold for the treatment of spinal cord injury

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Neural Regeneration Research 2013年第8期8卷 677-685页

作者： Dong Wang Yuhong Fan Jianjun Zhang Department of Neurosurgery Tianjin Fourth Central Hospital Department of Stomatology First Clinical CollegeHebei North University

Inhibition of neurite growth, which is in large part mediated by the Nogo-66 receptor, affects neural regeneration following bone marrow mesenchymal stem cell transplantation. The tissue engineering scaffold poly（D,L-lactide-co-glycolic acid） has good histocompatibility and can promote the growth of regenerating nerve fibers. The present study used small interfering RNA to silence Nogo-66 receptor gene expression in bone marrow mesenchymal stem cells and Schwann cells, which were subsequently transplanted with poly（D,L-lactide-co-glycolic acid） into the spinal cord lesion regions in rats. Simultaneously, rats treated with scaffold only were taken as the control group. Hematoxylin-eosin staining and immunohistochemistry revealed that at 4 weeks after transplantation, rats had good motor function of the hind limb after treatment with Nogo-66 receptor gene-silenced ceils prus the poly（O,L-lactide-co-glycolic acid） scaffold compared with rats treated with scaffold only, and the number of bone marrow mesenchymal stem cells and neuron-like cells was also increased. At 8 weeks after transplantation, horseradish peroxidase tracing and transmission electron microscopy showed a large number of unmyelinated and myelinated nerve fibers, as well as intact regenerating axonal myelin sheath following spinal cord hemisection injury. These experimental findings indicate that transplantation of Nogo-66 receptor gene-silenced bone marrow mesenchymal stem cells and Schwann cells plus a poly（D,L-lactide-co-glycolic acid） scaffold can significantly enhance axonal regeneration of spinal cord neurons and improve motor function of the extremities in rats following spinal cord injury.

关键词： neural regeneration spinal cord injury bone marrow mesenchymal stem cells Schwann cells poly(D,L-lactide-co-glycolic acid) Nogo-66 receptor gene rats gene silencing grants-supportedpaper photographs-containing paper neuroregeneration

Regenerative medicine strategies for chronic complete spinal cord injury

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Neural Regeneration Research 2024年第4期19卷 818-824页

作者： Shogo Hashimoto Narihito Nagoshi Masaya Nakamura Hideyuki Okano Department of Orthopedic Surgery Keio University School of Medicine Department of Physiology Keio University School of Medicine

spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various *** rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete ***,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental *** reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural ***,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe ***,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further ***,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.

关键词： cell transplantation chronic phase complete transection regenerative medicine spinal cord injury