Bioengineering in Action : Stratifying the immune reponse to biomaterials

保留字：老龄化与健康，分层医学，跨学科，生物工程，免疫反应骨科植入物，化学生物学摘要：这个学生奖学金的目的是提供一个独特的跨学科研究机会，在转化科学;学生将受益于双方提供的各种实验方法（纽卡斯尔和利兹），同时进行前沿假设驱动的转化研究，与MRC目前的交叉-切割主题，包括分层医学“每个病人的最佳治疗”。研究设计基于当前关于关节假体早期失效的根本原因和后果的重要问题，该问题导致约10%的手术，并且需要翻修手术，这对于医疗保健提供者和患者来说是昂贵的，因为发病率增加。将分别在纽卡斯尔和利兹（主管Joanne Tipper教授）开发一系列细胞、分子和生物工程体外技术，以定义和测量对金属离子化合物（如钴、镍和铬）以及金属和聚合物磨损颗粒的炎症反应。学生将在利兹大学（UoL）的医学与生物工程研究所实验室中使用简单的配置磨损模拟，从医用级钴铬合金和传统的超高分子量聚乙烯（UHMWPE）以及现代抗氧化剂聚乙烯中产生临床相关的（尺寸和形态）磨损颗粒。该设备具有独特的能力，能够通过关节面产生无菌、无内毒素的磨损颗粒，该关节面已通过髋关节模拟器和体内产生的磨损颗粒进行了确认。据信，颗粒表面特性在与细胞膜的相互作用中起着至关重要的作用，并且通常用于这些类型的研究中的模型颗粒不会引起与“真实的”磨损颗粒相同的细胞反应。将使用UoL开发的方法分离颗粒，并使用高分辨率冷场SEM进行表征。学生将在纽卡斯尔使用巨噬细胞，内皮细胞，成骨细胞和淋巴细胞开发体外模型。这些试验还将用于检测可能抑制或控制炎症反应的特定小分子抑制剂和拮抗剂。学生还将获得来自患者的关节液，以便与适当的临床数据一起进行分析。此外，电感耦合等离子体质谱法（ICP-MS）可用于测量滑液和颗粒润滑剂中的离子浓度，如铬和钴。失败的金属植入物周围的植入物周围组织通常被白细胞浸润，这可能导致观察到的免疫效应，包括炎性假瘤形成、软组织坏死和骨质溶解。这些因子对于白细胞粘附于内皮细胞是必需的，这是白细胞迁移到组织中所必需的。为了研究作用机制，学生将应用高度复杂的Cellix微流体平台来评估暴露于金属和聚合物生物材料后细胞粘附和迁移单层细胞;纽卡斯尔提供的这一突破性平台模拟微血管流动，而不是更常用的静态培养皿分析。学生还将应用基因组技术，使用市售的TLR 4 SNP特异性稳定细胞系，模拟患者对金属离子和生物材料颗粒的反应变异性。

Keywords: Ageing and Health, Stratified medicine, interdisciplinary, bioengineering, immune responses to orthopaedic implants, chemical-biologyAbstract: This studentship has been designed to provide a unique interdisciplinary research opportunity in translational science; the student will benefit from a diversity of experimental approaches provided by both partners (Newcastle and Leeds), whilst undertaking cutting-edge hypothesis-driven translational research that aligns itself with the MRC's current cross-cutting themes including stratified medicine 'The Best Treatment For Every Patient'. The study design is based around current important questions regarding the underlying causes and consequences of early failure of joint prostheses, a problem that results in approximately 10% of surgeries and necessitates a revision operation, which is costly to the healthcare provider and the patient in terms of increased morbidity. A range of cellular, molecular and bioengineering in vitro techniques will be developed at Newcastle and Leeds (supervisor Professor Joanne Tipper), respectively, to define and measure the inflammatory responses to metal ions compounds such as cobalt, nickel and chromium, and metal and polymer wear particles. The student will generate clinically-relevant (size and morphology) wear particles from medical grade cobalt chromium alloy and conventional ultra-high molecular weight polyethylene (UHMWPE), as well as modern anti-oxidant UHMWPEs using simple configuration wear simulation in the Institute of Medical & Biological Engineering laboratories at the University of Leeds (UoL). This equipment allows the unique capability of generating sterile, endotoxin-free wear particles by articulation that have been validated against hip simulator and in vivo generated wear particles. It is believed that particle surface characteristics play a crucial role in interactions with the cellular membrane and model particles that are often used in these types of studies do not elicit the same responses from cells as "real" wear particles. Particles will be isolated using methods developed at the UoL and characterised using high resolution cold field SEM. The student will develop in-vitro models using macrophages, endothelial cells, osteoblasts and lymphocytes at Newcastle. These assays will also be utilised to test specific small molecule inhibitors and antagonists which potentially dampen down or control the inflammatory response. The student will also have access to joint fluid from patients for analysis alongside appropriate clinical data. Additionally, inductively coupled plasma mass spectrophotometry (ICP-MS) is available to allow the measurement of ion concentrations such as chromium and cobalt in synovial fluid and particle lubricants. Peri-implant tissues around a failed metal implant are often infiltrated by leukocytes which may cause observed immunological effects, including inflammatory pseudotumour formation, soft tissue necrosis and osteolysis. These factors are essential for leukocyte adhesion to endothelium, which is required for leukocyte migration into tissues. In order to study the mechanism of action the student will apply a highly sophisticated Cellix microfluidics platform to assess cell adhesion to, and migration across monolayers of cells after exposure to metal and polymer biomaterials; this ground breaking platform available at Newcastle simulates microvascular flow as opposed to the more commonly used static petri dish-based assays. The student will also apply genomic techniques, using commercially available TLR4 SNP-specific stable cells lines, to model patient variability in response to metal ions and biomaterial particles.