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; 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.

这项研究的主要目的：这项研究的目的是了解为什么人造臀部和膝盖有时会过早地失败。这将通过结合实验室，临床和工程学科来确定导致髋关节和膝盖植入物疼痛和失败的不良反应的原因。当人造臀部和膝盖在患者体内工作时，它们会释放磨损碎片。可以理解，这些颗粒会导致植入物失败，但是确切的原因是为什么这是未知的，我们的研究问题是：为什么颗粒磨损碎屑会导致植入物失败，我们可以为现有患者预测这一点，以使其安全吗？总体方法是使用新颖的体外方法来模拟炎症性和骨质反应，以模拟Vivo现实的情况。这是双重的：（1）创建无菌磨损颗粒，以研究几种类型的聚合物，包括下一代植入聚合物，（2）开发一个真正代表性的体外细胞模型，以研究患者植入剂结构域以比较不同类型的碎屑并研究生物学反应。随后将（3）开发一种简单的床边方法来评估未来植入物失败的风险。我们打算回答的研究问题是； （a）临床上相关的磨损碎屑可以在体外人类巨噬细胞模型中诱导促炎的表型变化吗？ （b）是否能够在体外人类成骨细胞模型中引起造成溶骨反应的临床相关磨损碎片？ （c）可以从患者样品中分离出碎屑并使用纳米斜线颗粒跟踪分析进行表征吗？ （d）在修订时采集的人体组织样品是否显示出炎症标记的增加？新颖的科学和工程方法：使用在II类微生物学层中容纳的四层多方向销钉机器，将生成临床上相关的磨损碎片。碎片将使用纳米斜粒子跟踪分析和扫描电子显微镜（SEM）来表征碎片，以确定尺寸和形态。将进行内毒素和支原体测试，以确保不会污染产生的磨损碎屑，并且适合随后的体外实验。两种人类细胞系将用于研究产生的磨损碎屑的体外生物学作用，包括炎症和骨溶解。免疫调节和骨化过程的功能分析将与人类细胞系结合使用，以表征正在进行的生物学过程的机制。人体组织样品将在翻修手术时获取，并用于免疫组织化学，以染色特定的炎症标记和结构分析。在翻修手术期间收集的滑液的患者样品分析将用于碎片分离和蛋白质分泌分析。