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Clinical implications of linking microstructure, spatial biochemical, spatial biomechanical, and radiological features in ligamentum flavum degeneration 将黄韧带变性的微观结构、空间生物化学、空间生物力学和放射学特征联系起来的临床意义。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-08-09 DOI: 10.1002/jsp2.1365
Azril Azril, Kuo-Yuan Huang, Hsin-Yi Liu, Wei-An Liao, Wen-Lung Liu, Jonathan Hobley, Yeau-Ren Jeng

Background

The ligamentum flavum (LF) degeneration is a critical factor in spinal stenosis, leading to nerve compression and pain. Even with new treatment options becoming available, it is vital to have a better understanding of LF degeneration to ensure the effectiveness of these treatments.

Objective

This study aimed to provide insight into LF degeneration by examining the connections between various aspects of LF degeneration, including histology, microstructure, chemical composition, and biomechanics.

Method

We analyzed 30 LF samples from 27 patients with lumbar vertebrae, employing magnetic resonance imaging (MRI) to link lumbar disc degeneration grades with fibrosis levels in the tissue. X-ray diffraction (XRD) analysis assessed microstructural alterations in the LF matrix component due to degeneration progression. Instrumented nanoindentation combined with Raman spectroscopy explored the spatial microbiomechanical and biochemical characteristics of the LF's ventral and dorsal regions.

Results

Our outcomes revealed a clear association between the severity of LF fibrosis grades and increasing LF thickness. XRD analysis showed a rise in crystalline components and hydroxyapatite molecules with progressing degeneration. Raman spectroscopy detected changes in the ratio of phosphate, proteoglycan, and proline/hydroxyproline over the amide I band, indicating alterations in the extracellular matrix composition. Biomechanical testing demonstrated that LF tissue becomes stiffer and less extensible with increasing fibrosis.

Discussion

Notably, the micro-spatial assessment revealed the dorsal side of the LF experiencing more significant mechanical stress, alongside more pronounced biochemical and biomechanical changes compared to the ventral side. Degeneration of the LF involves complex processes that affect tissue histology, chemical composition, and biomechanics. It is crucial to fully understand these changes to develop new and effective treatments for spinal stenosis. These findings can improve diagnostic accuracy, identify potential biomarkers and treatment targets, guide personalized treatment strategies, advance tissue engineering approaches, help make informed clinical decisions, and educate patients about LF degeneration.

背景:黄韧带(LF)退变是椎管狭窄症的一个关键因素,可导致神经压迫和疼痛。即使有了新的治疗方案,也必须更好地了解黄韧带变性,以确保这些治疗的有效性:本研究旨在通过研究 LF 退化的各个方面(包括组织学、微观结构、化学成分和生物力学)之间的联系来深入了解 LF 退化:我们分析了27名腰椎病患者的30个腰椎间盘突出样本,利用磁共振成像(MRI)将腰椎间盘变性等级与组织中的纤维化水平联系起来。X 射线衍射(XRD)分析评估了腰椎间盘基质成分因退行性变而发生的微观结构变化。仪器纳米压痕与拉曼光谱相结合,探索了腰椎间盘突出症腹侧和背侧区域的空间微生物力学和生物化学特征:结果:我们的研究结果表明,低密度脂蛋白纤维化等级的严重程度与低密度脂蛋白厚度的增加之间存在明显的关联。XRD 分析表明,随着退化程度的加深,结晶成分和羟基磷灰石分子也在增加。拉曼光谱检测到磷酸、蛋白多糖和脯氨酸/羟脯氨酸在酰胺 I 波段上的比例发生了变化,表明细胞外基质成分发生了改变。生物力学测试表明,随着纤维化程度的增加,低密度脂蛋白组织变得更硬,伸展性更差:值得注意的是,微观空间评估显示,与腹侧相比,LF背侧承受着更大的机械应力,以及更明显的生化和生物力学变化。LF 的退化涉及影响组织学、化学成分和生物力学的复杂过程。充分了解这些变化对于开发新的、有效的椎管狭窄治疗方法至关重要。这些发现可以提高诊断的准确性,确定潜在的生物标记物和治疗目标,指导个性化治疗策略,推动组织工程方法的发展,帮助做出明智的临床决策,并对患者进行有关 LF 退化的教育。
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引用次数: 0
Biomolecular therapies for chronic discogenic low back pain: A narrative review 治疗慢性椎间盘源性腰痛的生物分子疗法:叙述性综述。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-08-06 DOI: 10.1002/jsp2.1345
Imke Rudnik-Jansen, Sanda van Kruining Kodele, Laura Creemers, Bert Joosten

Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD-LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra-cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long-term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD-LBP and summarizes effects of therapies aimed for CD-LBP with special emphasis on chronic pain. Approaches based on blocking pro-inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD-LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in-depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD-LBP could help narrow the gap between the pre-clinical bench and clinical bedside for novel CD-LBP therapeutics and optimize pain treatment.

椎间盘(IVD)退变引起的慢性腰背痛(又称慢性椎间盘源性腰背痛(CD-LBP))是最常见的肌肉骨骼疾病之一。IVD 的退变过程(如炎症和细胞外基质分解)会导致神经营养素的释放。局部神经营养素水平的升高会刺激感觉神经元的萌发和神经支配。此外,与邻近背根神经节直接相连的萌发的感觉神经会增加小胶质细胞的活化,从而导致疼痛的维持和慢性化。目前的疼痛治疗方法不足以或不适合长期使用。此外,大多数针对椎间盘退变潜在发病机制的治疗方法都侧重于修复和再生,而忽视了慢性疼痛。生物分子疗法如何影响退行性 IVD 环境、疼痛信号级联以及感觉神经元的神经支配和兴奋性往往仍不清楚。本综述探讨了 CD-LBP 的慢性疼痛治疗这一相对欠缺探索的领域,总结了针对 CD-LBP 的疗法的效果,并特别强调了慢性疼痛。事实证明,基于阻断促炎介质或神经营养素活性的方法会阻碍神经元向椎间盘的生长。此外,细胞外基质成分或移植间充质干细胞的组织再生和神经抑制特性也是潜在的有趣生物分子方法,不仅能阻止 IVD 退化,还能阻碍痛觉敏感化。目前,大多数生物分子疗法都是基于急性 IVD 退化模型,因此不能反映 CD-LBP 患者临床慢性疼痛的真实情况。未来的研究应着眼于调查治疗干预措施对包含已建立的感觉神经生长的慢性退化椎间盘的影响。深入了解生物分子疗法对 CD-LBP 患者疼痛(慢性化)途径和疼痛缓解的影响,有助于缩小新型 CD-LBP 治疗方法的临床前研究与临床治疗之间的差距,优化疼痛治疗。
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引用次数: 0
The potential effect of romosozumab on perioperative management for instrumentation surgery 罗莫单抗对器械手术围手术期管理的潜在影响。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-08-05 DOI: 10.1002/jsp2.1356
Koji Ishikawa, Soji Tani, Tomoaki Toyone, Koki Tsuchiya, Tomoko Towatari, Yusuke Oshita, Ryo Yamamura, Kazuki Wada, Takashi Nagai, Toshiyuki Shirahata, Katsunori Inagaki, Kudo Yoshifumi

Background

Age-related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3-month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)-based Finite Element Method (FEM).

Methods

This open-labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual-energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post-treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P-vBMD) and vertebral body (V-vBMD).

Results

Romosozumab treatment led to significant gains in P-vBMD, and V-vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group.

Conclusion

Romosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post-operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management.

背景:与年龄相关的骨骼健康变化会增加接受骨科手术的老年患者出现并发症的风险。骨质疏松症是确保器械手术成功的关键治疗目标。骨科手术中的药物干预,尤其是新药罗莫司单抗的疗效尚不清楚。我们旨在使用基于定量计算机断层扫描(QCT)的有限元方法(FEM),评估为期 3 个月的罗莫索单抗治疗对脊柱器械手术相关生物力学参数的影响:这项开放标签的前瞻性研究纳入了81名年龄在60至90岁之间、符合骨质疏松症标准并计划接受罗莫索单抗或艾地骨化醇治疗的患者。研究人员使用血液样本、双能量吸收测定法(DXA)和 QCT 对患者进行了评估。在基线和治疗后 3 个月,使用 FEM 对生物力学参数进行评估。主要终点是3个月时的生物力学参数,次要终点包括椎弓根周围(P-vBMD)和椎体(V-vBMD)区域体积骨矿密度的变化:结果:罗莫索单抗治疗3个月后,P-vBMD和V-vBMD均明显高于埃尔德卡西妥。值得注意的是,与埃尔德钙化醇组相比,罗莫索单抗组在3个月时通过FEM估算的所有生物力学参数都有了更大的改善:结论:罗莫索单抗能明显增加区域vBMD和生物力学参数,在减少接受骨科器械手术的骨质疏松症患者的术后并发症方面具有潜在的临床益处。本研究强调了罗莫司单抗治疗的新优势,并提倡进一步研究其在围手术期管理中的有效性。
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引用次数: 0
Cryopreserving the intact intervertebral disc without compromising viability 冷冻保存完整的椎间盘,同时不影响其存活能力。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-08-05 DOI: 10.1002/jsp2.1351
Ward Shalash, Ryan Forcier, Adam Z. Higgins, Morgan B. Giers

Background

Tissue cryopreservation requires saturation of the structure with cryoprotectants (CPAs) that are also toxic to cells within a short timeframe unless frozen. The race between CPA delivery and cell death is the main barrier to realizing transplantation banks that can indefinitely preserve tissues and organs. Unrealistic cost and urgency leaves less life-threatening ailments unable to capitalize on traditional organ transplantation systems that immediately match and transport unfrozen organs. For instance, human intervertebral discs (IVD) could be transplanted to treat back pain or used as ex vivo models for studying regenerative therapies, but both face logistical hurdles in organ acquisition and transport. Here we aimed to overcome those challenges by cryopreserving intact IVDs using compressive loading and swelling to accelerate CPA delivery.

Methods

CPAs were tested on bovine nucleus pulposus cells to determine the least cytotoxic solution. Capitalizing on our CPAs Computed Tomography (CT) contrast enhancement, we imaged and quantified saturation time in intact bovine IVDs under different conditions in a bioreactor. Finally, the entire protocol was tested, including 1 week of frozen storage, to confirm tissue viability in multiple IVD regions after thawing.

Results

Results showed cryopreserving medium containing dimethyl sulfoxide and ethylene glycol gave over 7.5 h before cytotoxicity. While non-loaded IVDs required over 3 days to fully saturate, a dynamic loading protocol followed by CPA addition and free-swelling decreased saturation time to <5 h. After cryopreserving IVDs for 1 week with the optimized CPA and permeation method, all IVD regions had 85% cell viability, not significantly different from fresh unfrozen controls.

Conclusions

This study created a novel solution to a roadblock in IVD research and development. Using post-compression swelling CPA can be delivered to an intact IVD over 20× more quickly than previous methods, enabling cryopreservation of the IVD with no detectable loss in cell viability.

背景:组织冷冻保存需要用冷冻保护剂(CPAs)使组织结构达到饱和,除非冷冻,否则这些保护剂在短时间内也会对细胞产生毒性。CPA 给药与细胞死亡之间的竞争是实现可无限期保存组织和器官的移植库的主要障碍。不现实的成本和紧迫性使得生命威胁较小的疾病无法利用传统的器官移植系统,因为传统的器官移植系统可以立即匹配和运输未冷冻的器官。例如,人类椎间盘(IVD)可以通过移植来治疗背痛,或用作研究再生疗法的体外模型,但两者都面临器官获取和运输方面的后勤障碍。在此,我们旨在通过冷冻保存完整的 IVD,利用压缩加载和膨胀来加速 CPA 的输送,从而克服这些挑战:方法:在牛髓核细胞上测试 CPA,以确定细胞毒性最小的解决方案。利用 CPA 的计算机断层扫描(CT)对比增强功能,我们对生物反应器中不同条件下完整牛 IVD 的饱和时间进行了成像和量化。最后,对整个方案进行了测试,包括一周的冷冻储存,以确认解冻后多个 IVD 区域的组织存活率:结果表明,含有二甲亚砜和乙二醇的冷冻保存介质可在 7.5 小时后产生细胞毒性。未加载的 IVD 需要 3 天以上才能完全饱和,而动态加载方案在添加 CPA 和自由膨胀后,饱和时间缩短至结论:这项研究为解决 IVD 研发中的一个难题提供了新的解决方案。利用压缩后溶胀法将 CPA 运送到完整的 IVD 的速度比以前的方法快 20 倍以上,从而实现了 IVD 的冷冻保存,而且细胞活力不会出现可检测到的损失。
{"title":"Cryopreserving the intact intervertebral disc without compromising viability","authors":"Ward Shalash,&nbsp;Ryan Forcier,&nbsp;Adam Z. Higgins,&nbsp;Morgan B. Giers","doi":"10.1002/jsp2.1351","DOIUrl":"10.1002/jsp2.1351","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Tissue cryopreservation requires saturation of the structure with cryoprotectants (CPAs) that are also toxic to cells within a short timeframe unless frozen. The race between CPA delivery and cell death is the main barrier to realizing transplantation banks that can indefinitely preserve tissues and organs. Unrealistic cost and urgency leaves less life-threatening ailments unable to capitalize on traditional organ transplantation systems that immediately match and transport unfrozen organs. For instance, human intervertebral discs (IVD) could be transplanted to treat back pain or used as ex vivo models for studying regenerative therapies, but both face logistical hurdles in organ acquisition and transport. Here we aimed to overcome those challenges by cryopreserving intact IVDs using compressive loading and swelling to accelerate CPA delivery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CPAs were tested on bovine nucleus pulposus cells to determine the least cytotoxic solution. Capitalizing on our CPAs Computed Tomography (CT) contrast enhancement, we imaged and quantified saturation time in intact bovine IVDs under different conditions in a bioreactor. Finally, the entire protocol was tested, including 1 week of frozen storage, to confirm tissue viability in multiple IVD regions after thawing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Results showed cryopreserving medium containing dimethyl sulfoxide and ethylene glycol gave over 7.5 h before cytotoxicity. While non-loaded IVDs required over 3 days to fully saturate, a dynamic loading protocol followed by CPA addition and free-swelling decreased saturation time to &lt;5 h. After cryopreserving IVDs for 1 week with the optimized CPA and permeation method, all IVD regions had 85% cell viability, not significantly different from fresh unfrozen controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study created a novel solution to a roadblock in IVD research and development. Using post-compression swelling CPA can be delivered to an intact IVD over 20× more quickly than previous methods, enabling cryopreservation of the IVD with no detectable loss in cell viability.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Flexible support material maintains disc height and supports the formation of hydrated tissue engineered intervertebral discs in vivo 柔性支撑材料可保持椎间盘高度,并支持体内水合组织工程椎间盘的形成。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-08-05 DOI: 10.1002/jsp2.1363
Alikhan B. Fidai, Byumsu Kim, Marianne Lintz, Sertac Kirnaz, Pravesh Gadjradj, Blake I. Boadi, Maho Koga, Ibrahim Hussain, Roger Härtl, Lawrence J. Bonassar

Background

Mechanical augmentation upon implantation is essential for the long-term success of tissue-engineered intervertebral discs (TE-IVDs). Previous studies utilized stiffer materials to fabricate TE-IVD support structures. However, these materials undergo various failure modes in the mechanically challenging IVD microenvironment. FlexiFil (FPLA) is an elastomeric 3D printing filament that is amenable to the fabrication of support structures. However, no present study has evaluated the efficacy of a flexible support material to preserve disc height and support the formation of hydrated tissues in a large animal model.

Methods

We leveraged results from our previously developed FE model of the minipig spine to design and test TE-IVD support cages comprised of FPLA and PLA. Specifically, we performed indentation to assess implant mechanical response and scanning electron microscopy to visualize microscale damage. We then implanted FPLA and PLA support cages for 6 weeks in the minipig cervical spine and monitored disc height via weekly x-rays. TE-IVDs cultured in FPLA were also implanted for 6 weeks with weekly x-rays and terminal T2 MRIs to quantify tissue hydration at study endpoint.

Results

Results demonstrated that FPLA cages withstood nearly twice the deformation of PLA without detrimental changes in mechanical performance and minimal damage. In vivo, FPLA cages and stably implanted TE-IVDs restored native disc height and supported the formation of hydrated tissues in the minipig spine. Displaced TE-IVDs yielded disc heights that were superior to PLA or discectomy-treated levels.

Conclusions

FPLA holds great promise as a flexible and bioresorbable material for enhancing the long-term success of TE-IVD implants.

背景:植入后的机械增强对组织工程椎间盘(TE-IVDs)的长期成功至关重要。以往的研究利用较硬的材料来制造 TE-IVD 支撑结构。然而,这些材料在具有机械挑战性的 IVD 微环境中会出现各种失效模式。FlexiFil(FPLA)是一种弹性三维打印长丝,可用于制造支撑结构。然而,目前还没有研究评估过柔性支撑材料在大型动物模型中保持椎间盘高度和支持水合组织形成的功效:我们利用之前开发的迷你猪脊柱有限元模型的结果,设计并测试了由 FPLA 和 PLA 组成的 TE-IVD 支撑笼。具体来说,我们采用压痕法评估植入物的机械响应,并用扫描电子显微镜观察微观损伤。然后,我们在小鼠颈椎中植入FPLA和PLA支撑笼6周,并每周通过X光片监测椎间盘高度。在FPLA中培养的TE-IVD也被植入6周,每周进行一次X光检查和终端T2 MRI检查,以量化研究终点时的组织水合情况:结果表明,FPLA保持架可承受近两倍于聚乳酸的变形,而机械性能不会发生有害变化,且损伤极小。在体内,FPLA保持架和稳定植入的TE-IVDs恢复了原生椎间盘高度,并支持水合组织在迷你猪脊柱中的形成。移位的 TE-IVDs 所产生的椎间盘高度优于 PLA 或椎间盘切除术处理过的水平:FPLA作为一种灵活的生物可吸收材料,在提高TE-IVD植入物的长期成功率方面大有可为。
{"title":"Flexible support material maintains disc height and supports the formation of hydrated tissue engineered intervertebral discs in vivo","authors":"Alikhan B. Fidai,&nbsp;Byumsu Kim,&nbsp;Marianne Lintz,&nbsp;Sertac Kirnaz,&nbsp;Pravesh Gadjradj,&nbsp;Blake I. Boadi,&nbsp;Maho Koga,&nbsp;Ibrahim Hussain,&nbsp;Roger Härtl,&nbsp;Lawrence J. Bonassar","doi":"10.1002/jsp2.1363","DOIUrl":"10.1002/jsp2.1363","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mechanical augmentation upon implantation is essential for the long-term success of tissue-engineered intervertebral discs (TE-IVDs). Previous studies utilized stiffer materials to fabricate TE-IVD support structures. However, these materials undergo various failure modes in the mechanically challenging IVD microenvironment. FlexiFil (FPLA) is an elastomeric 3D printing filament that is amenable to the fabrication of support structures. However, no present study has evaluated the efficacy of a flexible support material to preserve disc height and support the formation of hydrated tissues in a large animal model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We leveraged results from our previously developed FE model of the minipig spine to design and test TE-IVD support cages comprised of FPLA and PLA. Specifically, we performed indentation to assess implant mechanical response and scanning electron microscopy to visualize microscale damage. We then implanted FPLA and PLA support cages for 6 weeks in the minipig cervical spine and monitored disc height via weekly x-rays. TE-IVDs cultured in FPLA were also implanted for 6 weeks with weekly x-rays and terminal T2 MRIs to quantify tissue hydration at study endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Results demonstrated that FPLA cages withstood nearly twice the deformation of PLA without detrimental changes in mechanical performance and minimal damage. In vivo, FPLA cages and stably implanted TE-IVDs restored native disc height and supported the formation of hydrated tissues in the minipig spine. Displaced TE-IVDs yielded disc heights that were superior to PLA or discectomy-treated levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>FPLA holds great promise as a flexible and bioresorbable material for enhancing the long-term success of TE-IVD implants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Collagen integrity of the annulus fibrosus in degenerative disc disease individuals quantified with collagen hybridizing peptide 用胶原杂交肽量化椎间盘退行性病变患者纤维环的胶原完整性。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-31 DOI: 10.1002/jsp2.1359
Manmeet S. Dhiman, Taylor J. Bader, Dragana Ponjevic, Paul T. Salo, David A. Hart, Ganesh Swamy, John R. Matyas, Neil A. Duncan

Introduction

Degenerative disc disease (DDD) is accompanied by structural changes in the intervertebral discs (IVD). Extra-cellular matrix degradation of the annulus fibrosus (AF) has been linked with degeneration of the IVD. Collagen is a vital component of the IVD. Collagen hybridizing peptide (CHP) is an engineered protein that binds to degraded collagen, which we used to quantify collagen damage in AF. This method was used to compare AF samples obtained from donors with no DDD to AF samples from patients undergoing surgery for symptomatic DDD.

Methods

Fresh AF tissue was embedded in an optimal cutting temperature compound and cryosectioned at a thickness of 8 μm. Hematoxylin and Eosin staining was performed on sections for general histomorphological assessment. Serial sections were stained with Cy3-conjugated CHP and the mean fluorescence intensity and areal fraction of Cy3-positive staining were averaged for three regions of interest (ROI) on each CHP-stained section.

Results

Increases in mean fluorescence intensity (p = 0.0004) and percentage of positively stained area (p = 0.00008) with CHP were detected in DDD samples compared to the non-DDD samples. Significant correlations were observed between mean fluorescence intensity and percentage of positively stained area for both non-DDD (R = 0.98, p = 5E-8) and DDD (R = 0.79, p = 0.0012) samples. No significant differences were detected between sex and the lumbar disc level subgroups of the non-DDD and DDD groups. Only tissue pathology (non-DDD versus DDD) influenced the measured parameters. No three-way interactions between tissue pathology, sex, and lumbar disc level were observed.

Discussion and Conclusions

These findings suggest that AF collagen degradation is greater in DDD samples compared to non-DDD samples, as evidenced by the increased CHP staining. Strong positive correlations between the two measured parameters suggest that when collagen degradation occurs, it is detected by this technique and is widespread throughout the tissue. This study provides new insights into the structural alterations associated with collagen degradation in the AF that occur during DDD.

导言:椎间盘退行性疾病(DDD)伴随着椎间盘(IVD)结构的变化。纤维环(AF)细胞外基质的降解与 IVD 的退化有关。胶原蛋白是 IVD 的重要组成部分。胶原杂交肽(CHP)是一种能与降解胶原结合的工程蛋白,我们用它来量化 AF 中的胶原损伤。我们用这种方法比较了从无 DDD 的供体处获得的房颤样本和从因症状性 DDD 而接受手术的患者处获得的房颤样本:方法:将新鲜的心房颤动组织包埋在最佳切割温度的化合物中,然后冷冻切片,厚度为 8 μm。对切片进行苏木精和伊红染色,以进行一般组织形态学评估。用 Cy3 结合的 CHP 对连续切片进行染色,并对每个 CHP 染色切片上的三个感兴趣区(ROI)的平均荧光强度和 Cy3 阳性染色的面积分数进行平均:与非 DDD 样本相比,在 DDD 样本中检测到 CHP 平均荧光强度(p = 0.0004)和阳性染色面积百分比(p = 0.00008)的增加。在非滴滴涕样本(R = 0.98,p = 5E-8)和滴滴涕样本(R = 0.79,p = 0.0012)中,平均荧光强度和阳性染色面积百分比之间存在显著相关性。非DDD 组和 DDDD 组的性别和腰椎间盘水平亚组之间未发现明显差异。只有组织病理学(非腰椎间盘突出症与腰椎间盘突出症)对测量参数有影响。没有观察到组织病理学、性别和腰椎间盘水平之间的三方交互作用:这些研究结果表明,与非DDD样本相比,DDD样本的AF胶原降解程度更高,CHP染色增加就是证明。两个测量参数之间的强正相关性表明,当胶原降解发生时,该技术可以检测到,并且在整个组织中广泛存在。这项研究为我们提供了新的视角,让我们了解在 DDD 过程中发生的与房颤胶原降解相关的结构改变。
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引用次数: 0
In silico modeling the potential clinical effect of growth factor treatment on the metabolism of human nucleus pulposus cells 生长因子治疗对人类髓核细胞新陈代谢的潜在临床效应的硅学建模。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-31 DOI: 10.1002/jsp2.1352
Emily E. McDonnell, Tara Ní Néill, Niamh Wilson, Stacey L. Darwish, Joseph S. Butler, Conor T. Buckley

Background

While growth factors have the potential to halt degeneration and decrease inflammation in animal models, the literature investigating the effect of dosage on human cells is lacking. Moreover, despite the completion of clinical trials using growth differentiation factor-5 (GDF-5), no results have been publicly released.

Aims

The overall objective was to quantitatively assess the effect of three clinically relevant concentrations of GDF-5 (0.25, 1, and 2 mg) as a therapeutic for disc regeneration.

Materials and methods

Firstly, this work experimentally determined the effects of GDF-5 concentration on the metabolic and matrix synthesis rates of human nucleus pulposus (NP) cells. Secondly, in silico modeling was employed to predict the subsequent regenerative effect of different GDF-5 treatments (± cells).

Results

This study suggests a trend of increased matrix synthesis with 0.25 and 1 mg of GDF-5. However, 2 mg of GDF-5 significantly upregulates oxygen consumption. Despite this, in silico models highlight the potential of growth factors in promoting matrix synthesis compared to cell-only treatments, without significantly perturbing the nutrient microenvironment.

Discussion

This work elucidates the potential of GDF-5 on human NP cells. Although the results did not reveal statistical differences across all doses, the variability and response among donors is an interesting finding. It highlights the complexity of human response to biological treatments and reinforces the need for further human research and personalized approaches. Furthermore, this study raises a crucial question about whether these potential biologics are more regenerative in nature or better suited as prophylactic therapies for younger patient groups.

Conclusion

Biological agents exhibit unique characteristics and features, demanding tailored development strategies and individualized assessments rather than a one-size-fits-all approach. Therefore, the journey to realizing the full potential of biological therapies is long and costly. Nonetheless, it holds the promise of revolutionizing spinal healthcare and improving the quality of life for patients suffering

背景:虽然生长因子在动物模型中具有阻止退化和减少炎症的潜力,但缺乏研究其剂量对人体细胞影响的文献。此外,尽管使用生长分化因子-5(GDF-5)的临床试验已经完成,但尚未公布任何结果。目的:总体目标是定量评估三种临床相关浓度的 GDF-5(0.25、1 和 2 毫克)作为椎间盘再生疗法的效果:首先,本研究通过实验确定了 GDF-5 浓度对人髓核细胞代谢率和基质合成率的影响。其次,采用硅学建模预测不同 GDF-5 处理(± 细胞)的后续再生效果:结果:这项研究表明,0.25 毫克和 1 毫克 GDF-5 有增加基质合成的趋势。然而,2 毫克 GDF-5 会显著增加耗氧量。尽管如此,与纯细胞处理相比,硅学模型强调了生长因子在促进基质合成方面的潜力,而不会对营养微环境造成明显干扰:本研究阐明了 GDF-5 对人类 NP 细胞的潜在作用。虽然结果并未显示所有剂量的统计学差异,但供体之间的差异和反应是一个有趣的发现。它凸显了人类对生物治疗反应的复杂性,并加强了进一步人类研究和个性化方法的必要性。此外,这项研究还提出了一个关键问题,即这些潜在的生物制剂是更具有再生性质,还是更适合作为年轻患者群体的预防性疗法:生物制剂具有独特的特性和特征,需要量身定制的开发战略和个性化评估,而不是一刀切的方法。因此,充分发挥生物疗法潜力的道路漫长而昂贵。不过,它有望彻底改变脊柱医疗保健,改善椎间盘源性背痛患者的生活质量。
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引用次数: 0
Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc 在椎间盘修复过程中,perlecan(HSPG2)发挥着多样化和多功能的作用。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-29 DOI: 10.1002/jsp2.1362
James Melrose, Farshid Guilak

Perlecan is a widely distributed, modular, and multifunctional heparan sulfate proteoglycan, which facilitates cellular communication with the extracellular environment to promote tissue development, tissue homeostasis, and optimization of biomechanical tissue functions. Perlecan-mediated osmotic mechanotransduction serves to regulate the metabolic activity of cells in tissues subjected to tension, compression, or shear. Perlecan interacts with a vast array of extracellular matrix (ECM) proteins through which it stabilizes tissues and regulates the proliferation or differentiation of resident cell populations. Here we examine the roles of the HS-proteoglycan perlecan in the normal and destabilized intervertebral disc. The intervertebral disc cell has evolved to survive in a hostile weight bearing, acidic, low oxygen tension, and low nutrition environment, and perlecan provides cytoprotection, shields disc cells from excessive compressive forces, and sequesters a range of growth factors in the disc cell environment where they aid in cellular survival, proliferation, and differentiation. The cells in mechanically destabilized connective tissues attempt to re-establish optimal tissue composition and tissue functional properties by changing the properties of their ECM, in the process of chondroid metaplasia. We explore the possibility that perlecan assists in these cell-mediated tissue remodeling responses by regulating disc cell anabolism. Perlecan's mechano-osmotic transductive property may be of potential therapeutic application.

Perlecan是一种分布广泛、模块化和多功能的硫酸肝素蛋白多糖,它能促进细胞与细胞外环境的交流,从而促进组织发育、组织平衡和生物力学组织功能的优化。Perlecan介导的渗透性机械传导可调节组织中细胞在拉力、压力或剪切力作用下的代谢活动。Perlecan与大量细胞外基质(ECM)蛋白相互作用,通过这些蛋白稳定组织并调节驻留细胞群的增殖或分化。在这里,我们研究了HS-蛋白聚糖perlecan在正常和失稳椎间盘中的作用。椎间盘细胞的进化是为了在恶劣的负重、酸性、低氧张力和低营养环境中生存,perlecan 提供细胞保护,保护椎间盘细胞免受过度压缩力的影响,并将一系列生长因子封闭在椎间盘细胞环境中,帮助细胞生存、增殖和分化。机械性失稳结缔组织中的细胞试图通过改变其 ECM 的特性,在软骨新生的过程中重建最佳的组织成分和组织功能特性。我们探讨了perlecan通过调节椎间盘细胞新陈代谢来协助这些细胞介导的组织重塑反应的可能性。Perlecan的机械渗透传导特性可能具有潜在的治疗用途。
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引用次数: 0
Three-dimensional fiber patterning in the annulus fibrosus can be derived from vertebral endplate topography 纤维环中的三维纤维图案可从椎体终板地形图中得出。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-25 DOI: 10.1002/jsp2.1361
Ali Raza, Gwynneth T. Howell, Arthur J. Michalek

Introduction

The annulus fibrosus (AF) of the Intervertebral disc (IVD) is composed of concentric lamellae of helically wound collagen fibers. Understanding the spatial variation of collagen fiber orientations in these lamellae, and the resulting material anisotropy, is crucial to predicting the mechanical behavior of the complete IVD.

Methods

This study builds on a prior model predicated on path-independent displacement of fiber endpoints during vertebral body growth to predict a complete, three-dimensional annulus fibrosus fiber network from a small number of subject-independent input parameters and vertebral endplate topographies obtained from clinical imaging. To evaluate the model, it was first fit to mid-plane fiber orientations obtained using polarized light microscopy in a population of bovine caudal discs for which computed tomography images vertebral endplates were also available. Additionally, the model was used to predict the trajectories based on human lumbar disc geometries and results were compared to previously reported data. Finally, the model was employed to investigate potential disc-related variations in fiber angle distributions.

Results

The model was able to accurately predict experimentally measured fiber distributions in both bovine and human discs using only endplate topography and three input parameters. Critically, the model recapitulated previously observed asymmetry between the inclinations of right- and left-handed fibers in the posterolateral aspect of the human AF. Level to level variation of disc height and aspect ratio in the human lumbar spine was predicted to affect absolute values of fiber inclination, but not this asymmetry.

Conclusion

Taken together these results suggest that patient-specific distributions of AF fiber orientation may be readily incorporated into computational models of the spine using only disc geometry and a small number of subject-independent parameters.

简介:椎间盘(IVD)的纤维环(AF)由螺旋缠绕的胶原纤维同心层组成。了解这些薄片中胶原纤维取向的空间变化以及由此产生的材料各向异性对于预测完整 IVD 的机械行为至关重要:本研究以先前的一个模型为基础,该模型以椎体生长过程中纤维端点的路径无关位移为前提,通过少量与受试者无关的输入参数和从临床成像中获得的椎体终板地形图来预测完整的三维纤维环网络。为了对该模型进行评估,首先对牛尾椎间盘的中平面纤维方向进行了拟合,并通过偏振光显微镜获得了这些椎间盘的计算机断层扫描图像椎体终板。此外,该模型还用于预测基于人体腰椎间盘几何形状的轨迹,并将结果与之前报告的数据进行比较。最后,该模型还用于研究纤维角度分布中与椎间盘相关的潜在变化:结果:仅使用终板地形图和三个输入参数,该模型就能准确预测牛椎间盘和人椎间盘中经实验测量的纤维分布。重要的是,该模型再现了之前观察到的人类房颤后外侧左右手纤维倾斜度的不对称。据预测,人体腰椎间盘高度和纵横比的水平变化会影响纤维倾斜度的绝对值,但不会影响这种不对称:总之,这些结果表明,只需使用椎间盘几何形状和少量与受试者无关的参数,就可以将患者特定的腰椎间盘突出纤维方向分布轻松纳入脊柱计算模型中。
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引用次数: 0
Experimental confirmation and bioinformatics reveal biomarkers of immune system infiltration and hypertrophy ligamentum flavum 实验证实和生物信息学揭示了免疫系统浸润和黄韧带肥厚的生物标志物。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-25 DOI: 10.1002/jsp2.1354
Fei Liu, Min Zhong, Lei Yang, Chao Song, Chaoqi Chen, Zhiwei Xu, Chi Zhang, Zhifa Li, Xiaofei Wu, Chen Jiang, Feng Chen, Qian Yan

Background

Hypertrophy ligamentum flavum is a prevalent chronic spinal condition that affects middle-aged and older adults. However, the molecular pathways behind this disease are not well comprehended.

Objective

The objective of this work is to implement bioinformatics techniques in order to identify crucial biological markers and immune infiltration that are linked to hypertrophy ligamentum flavum. Further, the study aims to experimentally confirm the molecular mechanisms that underlie the hypertrophy ligamentum flavum.

Methods

The corresponding gene expression profiles (GSE113212) were selected from a comprehensive gene expression database. The gene dataset for hypertrophy ligamentum flavum was acquired from GeneCards. A network of interactions between proteins was created, and an analysis of functional enrichment was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. An study of hub genes was performed to evaluate the infiltration of immune cells in patient samples compared to tissues from the control group. Finally, samples of the ligamentum flavum were taken with the purpose of validating the expression of important genes in a clinical setting.

Results

Overall, 27 hub genes that were differently expressed were found through molecular biology. The hub genes were found to be enriched in immune response, chemokine-mediated signaling pathways, inflammation, ossification, and fibrosis processes, as demonstrated by GO and KEGG studies. The main signaling pathways involved include the TNF signaling pathway, cytokine–cytokine receptor interaction, and TGF-β signaling pathway. An examination of immunocell infiltration showed notable disparities in B cells (naïve and memory) and activated T cells (CD4 memory) between patients with hypertrophic ligamentum flavum and the control group of healthy individuals. The in vitro validation revealed markedly elevated levels of ossification and fibrosis-related components in the hypertrophy ligamentum flavum group, as compared to the normal group.

Conclusion

The TGF-β signaling pathway, TNF signaling pathway, and related hub genes play crucial roles in the progression of ligamentum flavum hypertrophic. Our study may guide future research on fibrosis of the ligamentum flavum.

背景:黄韧带肥厚症是一种常见的慢性脊柱疾病,多发于中老年人。然而,人们对这种疾病背后的分子途径还不甚了解:这项工作的目的是采用生物信息学技术,以确定与黄韧带肥厚有关的关键生物标记和免疫浸润。此外,该研究还旨在通过实验证实黄韧带肥厚的分子机制:方法:从全面的基因表达数据库中筛选出相应的基因表达谱(GSE113212)。黄韧带肥厚的基因数据集来自 GeneCards。建立了蛋白质之间的相互作用网络,并利用京都基因和基因组百科全书(KEGG)和基因本体(GO)数据库进行了功能富集分析。对枢纽基因进行了研究,以评估与对照组组织相比,患者样本中免疫细胞的浸润情况。最后,还采集了黄韧带样本,以验证重要基因在临床环境中的表达情况:结果:通过分子生物学研究,共发现了 27 个表达不同的中心基因。通过 GO 和 KEGG 研究发现,这些中心基因主要集中在免疫反应、趋化因子介导的信号通路、炎症、骨化和纤维化过程中。涉及的主要信号通路包括 TNF 信号通路、细胞因子-细胞因子受体相互作用和 TGF-β 信号通路。对免疫细胞浸润的研究显示,肥厚性黄韧带患者与健康人对照组之间在 B 细胞(幼稚细胞和记忆细胞)和活化 T 细胞(CD4 记忆细胞)方面存在明显差异。体外验证显示,与正常组相比,黄韧带肥厚组的骨化和纤维化相关成分水平明显升高:结论:TGF-β信号通路、TNF信号通路及相关枢纽基因在黄韧带肥大症的进展中起着关键作用。我们的研究可为今后有关黄韧带纤维化的研究提供指导。
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引用次数: 0
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JOR Spine
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