Nanoparticles for the treatment of spinal cord injury

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Synthesis and Characterization of a Silica-Based Drug Delivery System for Spinal Cord Injury Therapy

Acute inflammation is a central component in the progression of spinal cord injury(SCI).Anti-inflammatory drugs used in the clinic are often administered systemically at high doses,which can paradoxically increase inflammation and result in drug toxicity.A cluster-like mesoporous silica/arctigenin/CAQK composite(MSN-FC@ARCG)drug delivery system was designed to avoid systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord.In this nanosystem,mesoporous silica was modified with the FITC fluorescent molecule and CAQK peptides that target brain injury and SCI sites.The size of the nanocarrier was kept at approximately 100 nm to enable penetration of the blood–brain barrier.Arctigenin,a Chinese herbal medicine,was loaded into the nanosystem to reduce inflammation.The in vivo results showed that MSN-FC@ARC-G could attenuate inflammation at the injury site.Behavior and morphology experiments suggested that MSN-FC@ARC-G could diminish local microenvironment damage,especially reducing the expression of interleukin-17(IL-17) and IL-17-related inflammatory factors,inhibiting the activation of astrocytes,thus protecting neurons and accelerating the recovery of SCI.Our study demonstrated that this novel,silica-based drug delivery system has promising potential for clinical application in SCI therapy.

Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury

Traumatic spinal cord injury is a devastating disorder chara cterized by sensory,motor,and autonomic dysfunction that seve rely compromises an individual's ability to perform activities of daily living.These adve rse outcomes are closely related to the complex mechanism of spinal cord injury,the limited regenerative capacity of central neurons,and the inhibitory environment fo rmed by traumatic injury.Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury.A number of therapeutic agents have been shown to improve the injury environment,mitigate secondary damage,and/or promote regeneration and repair.Among them,the spinal cord microcirculation has become an important target for the treatment of spinal cord injury.Drug inte rventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury.These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neuro ns,axons,and glial cells.This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury,including its structure and histopathological changes.Further,it summarizes the progress of drug therapies targeting the spinal cord mic rocirc ulation after spinal cord injury.

Hydrogel-based local drug delivery strategies for spinal cord repair

Spinal cord injury results in significant loss of motor, sensory, and autonomic functions. Although a wide range of therapeutic agents have been shown to attenuate secondary injury or promote regeneration/repair in animal models of spinal cord injury, clinical translation of these strategies has been limited, in part due to difficulty in safely and effectively achieving therapeutic concentrations in the injured spinal cord tissue. Hydrogelbased drug delivery systems offer unique opportunities to locally deliver drugs to the injured spinal cord with sufficient dose and duration, while avoiding deleterious side effects associated with systemic drug administration. Such local drug delivery systems can be readily fabricated from biocompatible and biodegradable materials. In this review, hydrogel-based strategies for local drug delivery to the injured spinal cord are extensively reviewed, and recommendations are made for implementation.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

A Model of Subarachnoid Cavity Drugs Perfusion and ItsClinical Application in Treatment of Spinal Cord Injury

An animal model of subarachnoid cavity drugs perfusion and its prelimilary clinical application in treatment of acute spinal cord injury (SCI) were reported.Analysis of the heart rate (HR), ECG, blood pressure (CVP, CAP ),cerebrospinal fluid (CSF) pressuer and CSF gas and pH values of lo healthy adultgoats during subarachnoid daxamethasone, verapamil perfusion showed that thismodel was safe and reliable. 26 patients with acute SCl were selected for a clinicalobseration. Good results were obtained in 7 cases who received this treatment of subarachnoid cavity perfusion with dexamethasone and verapamil.

Molecular approaches for spinal cord injury treatment

Injuries to the spinal cord result in permanent disabilities that limit daily life activities.The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries.Despite decades of research,there is still no efficient treatment for spinal cord injury.Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury.Among these,molecular compounds are currently being used for neurological recovery,with promising results.These molecules target the axon collapsed growth cone,the inhibitory microenvironment,the survival of neurons and glial cells,and the re-establishment of lost connections.In this review we focused on molecules that are being used,either in preclinical or clinical studies,to treat spinal cord injuries,such as drugs,growth and neurotrophic factors,enzymes,and purines.The mechanisms of action of these molecules are discussed,considering traumatic spinal cord injury in rodents and humans.

Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function after spinal cord injury

Methylprednisolone exhibits anti-inflammatory antioxidant properties, and rosiglitazone acts as an anti-inflammatory and antioxidant by activating peroxisome proliferator-activated receptor-y in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inflammatory process after spinal cord injury, a single drug cannot completely inhibit inflammation. Therefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function after secondary spinal cord injury. In this study, rats were intraperitoneally rejected with methylprednisolone （30 mg/kg） and rosiglitazone （2 mg/kg） at 1 hour after injury, and methylprednisolone （15 mg/kg） at 24 and 48 hours after injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inflammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better pro- moted recovery of neurological function after injury.

Bioinformatics analysis of ferroptosis in spinal cord injury

Ferroptosis plays a key role in aggravating the progression of spinal cord injury(SCI),but the specific mechanism remains unknown.In this study,we constructed a rat model of T10 SCI using a modified Allen method.We identified 48,44,and 27 ferroptosis genes that were differentially expressed at 1,3,and 7 days after SCI induction.Compared with the sham group and other SCI subgroups,the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower.These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression.Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI:STAT3,JUN,TLR4,ATF3,HMOX1,MAPK1,MAPK9,PTGS2,VEGFA,and RELA.Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3,JUN,TLR4,ATF3,HMOX1,PTGS2,and RELA mRNA levels were up-regulated and VEGFA,MAPK1 and MAPK9 mRNA levels were down-regulated.Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI.We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs,10 miRNAs,and 12 genes.Our results help further the understanding of the mechanism underlying ferroptosis in SCI.

载药外泌体在中枢神经系统疾病中的热点问题

背景:利用外泌体作为药物载体不仅可以精确靶向治疗部位,还能提高局部浓度,为药物进入中枢神经系统开辟了一条新途径。目的:探讨外泌体的生物发生、生物学功能,综述当前有关细胞外囊泡作为药物载体在中枢神经系统疾病治疗中的最新进展。方法:由第一作者检索Web of Science、Pub Med和中国知网数据库1976年1月至2024年1月发表的相关文献,以“exosomes,extracellular vesicles,central nervous system,drug delivery,ischemic stroke,Alzheimer’s disease,Parkinson’s disease,spinal cord injury,brain tumor”为英文检索词,以“外泌体,细胞外囊泡,中枢神经系统疾病,载药,脑卒中,阿尔兹海默病,帕金森病,脊髓损伤、脑肿瘤”为中文检索词,最终纳入94篇文献进行分析。结果与结论:(1)外泌体可以轻易通过血脑屏障输送蛋白质、代谢物和核酸到受体细胞中,调节细胞代谢。由于外泌体是由细胞分泌的小囊泡,具有更低的循环免疫原性,在体内循环中能够更少被巨噬细胞识别清除。(2)外泌体可以被设计为递送不同的治疗成分,包括RNA、蛋白质、化疗药物和免疫调节剂,能够将治疗成分传送至期望的目标。经过工程修饰的外泌体具有更好的靶向性,并且这种外泌体介导的传递免疫原性极低,有望为将来中枢神经系统疾病的精准治疗提供更加安全有效的方法。

Mesenchymal stem cell-derived exosomes as a new drug carrier for the treatment of spinal cord injury:A review

Spinal cord injury(SCI)is a devastating traumatic disease seriously impairing the quality of life in patients.Expectations to allow the hopeless central nervous system to repair itself after injury are unfeasible.Developing new approaches to regenerate the central nervous system is still the priority.Exosomes derived from mesenchymal stem cells(MSC-Exo)have been proven to robustly quench the inflammatory response or oxidative stress and curb neuronal apoptosis and autophagy following SCI,which are the key processes to rescue damaged spinal cord neurons and restore their functions.Nonetheless,MSC-Exo in SCI received scant attention.In this review,we reviewed our previous work and other studies to summarize the roles of MSC-Exo in SCI and its underlying mechanisms.Furthermore,we also focus on the application of exosomes as drug carrier in SCI.In particular,it combs the advantages of exosomes as a drug carrier for SCI,imaging advantages,drug types,loading methods,etc.,which provides the latest progress for exosomes in the treatment of SCI,especially drug carrier.

Role of inflammation in neurological damage and regeneration following spinal cord injury and its therapeutic implications

Spinal cord injury(SCI)is an incurable trauma that frequently results in partial or complete loss of motor and sensory function.Massive neurons are damaged after the initial mechanical insult.Secondary injuries,which are triggered by immunological and inflammatory responses,also result in neuronal loss and axon retraction.This results in defects in the neural circuit and a deficiency in the processing of information.Although inflammatory responses are necessary for spinal cord recovery,conflicting evidence of their contributions to specific biological processes have made it difficult to define the specific role of inflammation in SCI.This review summarizes our understanding of the complex role of inflammation in neural circuit events following SCI,such as cell death,axon regeneration and neural remodeling.We also review the drugs that regulate immune responses and inflammation in the treatment of SCI and discuss the roles of these drugs in the modulation of neural circuits.Finally,we provide evidence about the critical role of inflammation in facilitating spinal cord neural circuit regeneration in zebrafish,an animal model with robust regenerative capacity,to provide insights into the regeneration of the mammalian central nervous system.

1例罕见盐酸纳美芬用药不良反应及治疗经验分享

我院收治1例脊髓损伤合并顽固性神经病理性疼痛患者,缓慢滴注盐酸纳美芬(Nalmefene)注射液(规格:1ml:0.1mg)0.3mg溶于100ml氯化钠注射液静脉输液(30滴/分钟),输注约35ml左右时出现罕见过敏反应,主要表现为四肢湿冷、躁动、角弓反张、四肢震颤、胸腹部发紧痉挛、大声喊叫、强哭强笑、口面部及双手发红。患者出现症状后,立即停药,同时予心电监护、吸氧、大量补液、激素抗炎、镇静、利尿促排等综合治疗后逐渐好转,全程血压无降低,监测患者肝肾功能、心肌酶等均未见异常。本文结合患者病历资料分析了盐酸纳美芬的作用机制,及过敏后的全身反应及可能机制,分析了处置过程中的不足之处,同时完善科室内药物不良反应发生后的急救预案的制定,从而能及时有效救治、最大程度保证患者的安全,为临床脊髓损伤药物治疗提供一些思路。

督脉电针治疗大鼠全横断性脊髓损伤的实验研究

目的 :探讨督脉电针对大鼠全横断性脊髓损伤的行为和结构修复的影响。方法 :用BBB评分法和爬网格试验检测全横断性脊髓损伤及督脉电针治疗后大鼠的运动功能 ,荧光金逆行标记法检测再生神经元 ,用生长相关蛋白 43 (GAP 43 )免疫组织化学法观察脊髓损伤区周围神经元GAP 43的表达。结果 :督脉电针治疗后大鼠后肢运动功能有明显地恢复 ,损伤区脊髓组织退变减轻 ,躯体感觉运动区内锥体细胞层及红核内的神经元密度增大 ,脊髓组织内GAP 43阳性神经元增多 ,在脊髓横断头侧端灰质内、躯体运动感觉区及红核内有少量被标记细胞。结论 :督脉电针治疗可减轻脊髓损伤后的继发性损伤 。

电针八髎、会阳治疗脊髓损伤性尿潴留疗效观察

目的探寻治疗脊髓损伤性尿潴留的较佳疗法。方法将84例观察病例随机分为治疗组(46例)和对照组(38例)。治疗组采用电针八髎、会阳穴,对照组采用常规取穴电针治疗。结果治疗组总有效率为82.6%,痊愈率为43.5%;对照组分别为63.2%、23.7%。两组间差异有非常显著性意义(P<0.01)。结论电针八髎、会阳穴治疗脊髓损伤性尿潴留疗效优于常规取穴电针疗法。

电针预处理对兔脊髓缺血再灌注损伤细胞内Ca^(2+)变化的影响

目的 :探讨重复电针预处理诱导缺血耐受对脊髓缺血再灌注损伤保护作用的机制。方法 :76只雄性新西兰大白兔随机分成 4组 :对照组 (C组 ) ,戊巴比妥钠组 (SP组 ) ,假手术组 (S组 ) ,电针预处理组 (EA组 )。最后一次预处理后 2 4h ,阻闭肾下腹主动脉 ,制作兔脊髓缺血模型 ;S组动物手术操作同C组 ,但不阻闭腹主动脉。分别于阻闭后不同时相点测定细胞内Ca2 + 含量 ,并分别对动物后肢运动功能评分。结果 :EA组脊髓组织细胞内Ca2 + 含量显著低于C组和SP组各时相值 (P <0 0 1) ,神经功能评分EA组明显高于C组 (P <0 0 1) ,C组和SP组细胞内Ca2 + 和神经功能评分无显著性差异 (P >0 0 5 )。结论 :电针预处理具有降低脊髓组织细胞内Ca2 + 含量 ,防止Ca2 + 超载 ,稳定细胞内环境的能力 ,对腹主动脉阻断所致的脊髓缺血再灌注损伤具有良好的保护作用。

电针对脊髓损伤后星形胶质细胞增生的影响

目的探讨电针治疗脊髓损伤的机理。方法选用成年Wistar大鼠,Allen氏法制备脊髓损伤模型,分别应用督脉电针治疗3d、1w、2w或4w,以正常组和损伤组作对照。应用电镜、免疫组化、原位杂交显色观察星形胶质细胞的形态、数量的变化;应用逆转录聚合酶链反应(RT-PCR)检测损伤脊髓星形胶质细胞特异性标志蛋白胶质原纤维酸性蛋白(GFAP)mRNA表达变化。结果电镜观察,术后3d,损伤组星形胶质细胞肿胀明显;1w时见反应性增生,体积增大,数量增加;4w时,形态基本正常。电针组胶质反应轻,线粒体、核糖体增多,常见吞噬现象。免疫组化见,同一动物星形胶质细胞数灰质多于白质,尾侧多于头侧;组间比较阳性细胞数损伤组明显多于电针组,且损伤范围大,胶质界膜明显。原位杂交结果与免疫组化结果类似。电泳结果表明损伤早期电针组GFAPmRNA表达明显低于损伤组。结论电针治疗可抑制脊髓损伤后星形胶质细胞反应性增生,防止胶质瘢痕形成,创造有利于神经再生的微环境。

脊髓康对脊髓损伤大鼠Nogo-66受体NgR表达的影响

背景:研究发现,脊髓损伤后髓鞘相关抑制分子的产生是影响轴突再生微环境的重要原因。中医药具有多因素、多靶点的优点,正逐步成为改善神经再生微环境的研究热点。目的:探索中药脊髓康对脊髓损伤后Nogo-66受体Ng R表达的影响。方法:144只大鼠随机等分为6组,假手术组、模型组、强的松组、脊髓康高、中、低剂量组,每组24只。后5组以改良Allen’s法建立脊髓损伤动物模型。强的松组大鼠每天给予0.06 g/kg醋酸泼尼松灌胃,1次/d。脊髓康低中高剂量组大鼠每天给予12.5,25,50 g/kg脊髓康灌胃,1次/d。假手术组和模型组大鼠每天给予20 m L生理盐水灌胃,1次/d。各组动物均连续给药至动物处死。结果与结论:与模型组相比,强的松组及脊髓康低中剂量组大鼠脊髓组织中Ng R蛋白及m RNA表达水平均显著降低。提示脊髓康可促进大鼠脊髓损伤后神经功能的恢复,可有效抑制脊髓损伤区Ng R蛋白的表达,从而抑制不利于神经再生的因素,进一步改善神经再生的微环境。

急性颈脊髓损伤患者肺部感染的危险因素及病原菌分析

目的：探讨急性颈脊髓损伤患者肺部感染的危险因素与病原菌分布特点及耐药性。方法：2010年1月-2014年12月收治急性颈脊髓损伤患者527例,发生肺部感染83例,应用Logistic回归方法分析肺部感染与颈脊髓损伤部位（C1-C4为高位损伤,C5-C7为低位损伤）、ASIA分级、气管切开及机械通气的相关性,并分析肺部感染患者痰细菌培养的细菌种类、株数及耐药率。结果：ASIA分级A级患者158例（30.0%）,其中高位损伤43例（8.2%）,均行气管切开、呼吸机辅助呼吸,发生肺部感染39例（90.7%）;低位损伤115例（21.8%）,52例行气管切开,21例行呼吸机辅助呼吸患者中肺部感染16例（76.2%）,31例未行呼吸机辅助呼吸患者中肺部感染7例（22.6%）。B级103例（19.5%）,其中高位损伤27例（5.1%）,19例气管切开、呼吸机辅助呼吸,肺部感染12例（63.2%）;低位损伤76例（14.4%）,27例气管切开,18例呼吸机辅助呼吸患者中肺部感染2例（11.1%）,9例未行呼吸机辅助呼吸患者未发生肺部感染。C级83例、D级183例,均未行气管切开及呼吸机辅助呼吸,均未发生肺部感染。Logistic回归分析显示高位颈髓损伤、ASIA A级损伤及机械通气均是急性颈脊髓损伤患者肺部感染发生的危险因素（P≤0.001）,气管切开对肺部感染的发生率无显著性影响（P=0.07）。83例肺部感染患者痰标本培养出细菌117株,其中多重耐药菌75株（64.1%）;其中非发酵G-菌（铜绿假单胞菌、洛菲不动杆菌、鲍曼不动杆菌、嗜麦芽窄食单胞菌、臭鼻克雷伯菌、液化沙雷菌、苯丙酮酸莫拉菌、产碱假单胞菌）76株（65.0%）,其中59株（77.6%）多重耐药;金黄色葡萄球菌23株（13.8%）,其中耐甲氧西林金黄色葡萄球菌（MRSA）7株（30.4%）;肠杆菌（产气肠杆菌、阴沟肠杆菌）12株（10.3%）,其中5株（41.7%）多重耐药。结论：高位、完全性颈髓损伤及机械通气是急性颈脊髓损伤患者肺部感染发生的相关危险因素,肺部感染的病原菌主要是多重耐药非发酵G-菌,MRSA及多重耐药肠杆菌亦占有一定比例。