Reducing the failure rate of artificial replacement hips and knees by understanding the mechanism of adverse biological reactions that currently cause

通过了解目前引起的不良生物反应机制，降低人工髋关节和膝关节置换的失败率

• 批准号: 2281157
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2281157
• 关键词: Reducing; failure; rate; artificial; replacement

Key aims of the research: The aim of this research is to understand why artificial hips and knees sometimes fail prematurely in patients. This will be done by combining laboratory, clinical and engineering disciplines to find out what causes the adverse reactions that results in pain and failure of hip and knee implants. When artificial hips and knees operate in the patient's body, they release particles of wear debris. It is understood that these particles contribute to the implant failing, but exactly why that is unknown and our research question is: Why does particulate wear debris cause implants to fail and can we predict this for existing patients in order to make them safe?The overall approach is to use a novel in vitro methodology to simulate inflammatory and osteolytic responses that more closely matches reality in vivo conditions. This is twofold: (1) create aseptic wear particles for study of several types of polymer including the next generation of implant polymers, and (2) develop a truly representative in vitro cell model to study the patient-implant domain to compare different types of debris and investigate the biological responses. These will be followed by (3) developing a simple bedside method to assess the patient risk of implant failure in the future.The research questions we intend to answer are; (a) Can clinically relevant wear debris induce proinflammatory phenotypic changes in a human macrophage model in vitro? (b) Are clinically relevant wear debris capable of eliciting osteolytic responses in an in vitro human osteoblast cell model? (c) Can wear debris be isolated from patient samples and characterised using NanoSight Particle Tracking analysis? (d) Do human tissue samples taken at the point of revision show an increase in inflammatory markers?Novel science and engineering methodology: Clinically relevant wear debris will be generated using a four-station multi-directional pin-on-plate machine housed in a class II microbiology laminar flow cabinet. Debris will be characterised using NanoSight Particle Tracking analysis and scanning electron microscopy (SEM) to determine size and morphology. Endotoxin and mycoplasma testing will be carried out in order to ensure that the wear debris generated is not contaminated and will be suitable for subsequent in vitro experiments. Two human cell lines will be used to investigate the in vitro biological effects of the generated wear debris including inflammation and osteolysis. Functional analyses of immunomodulatory and osteolytic processes will be used in conjunction with the human cell lines in order to characterise the mechanism of ongoing biological processes. Human tissue samples will be acquired at the point of revision surgery and used for immunohistochemistry in order to stain for specific inflammatory markers as well as structural analysis. Patient sample analysis of synovial fluid collected during revision surgery will be used for debris isolation and protein secretion analysis.

研究的主要目的：本研究的目的是了解为什么人工髋关节和膝关节有时会在患者中过早失效。这将通过结合实验室，临床和工程学科来完成，以找出导致髋关节和膝关节植入物疼痛和失败的不良反应的原因。当人工髋关节和膝关节在患者体内运行时，它们会释放出磨损碎屑颗粒。据了解，这些颗粒会导致植入物失效，但具体原因尚不清楚，我们的研究问题是：为什么颗粒磨损碎屑会导致植入物失效，我们能否预测现有患者的这种情况，以使其安全？总体方法是使用一种新的体外方法来模拟炎症和溶骨性反应，更接近于体内条件下的实际情况。这是双重的：（1）创建无菌磨损颗粒，用于研究几种类型的聚合物，包括下一代植入物聚合物，以及（2）开发真正具有代表性的体外细胞模型，用于研究患者-植入物区域，以比较不同类型的碎片并研究生物学反应。我们打算回答的研究问题是：（a）临床相关的磨损碎屑能否在体外诱导人巨噬细胞模型中的促炎表型变化？(b)临床相关磨屑是否能够在体外人成骨细胞模型中引发溶骨性反应？(c)是否可以从患者样本中分离出磨屑并使用NanoSight颗粒跟踪分析进行表征？(d)在翻修时采集的人体组织样本是否显示炎症标志物增加？新的科学和工程方法：将使用II类微生物层流柜中的四站多向钉板机生成临床相关磨屑。将使用NanoSight颗粒跟踪分析和扫描电子显微镜（SEM）对碎屑进行表征，以确定尺寸和形态。将进行内毒素和支原体试验，以确保产生的磨屑不受污染，并适用于后续体外实验。将使用两种人类细胞系研究所产生磨屑的体外生物学效应，包括炎症和骨质溶解。免疫调节和溶骨过程的功能分析将与人细胞系结合使用，以阐明正在进行的生物学过程的机制。将在翻修手术时采集人体组织样本，并用于免疫组织化学，以便对特定炎症标志物进行染色以及结构分析。翻修手术期间收集的滑液患者样本分析将用于碎片分离和蛋白分泌分析。