Bioengineering in Action : Stratifying the immune reponse to biomaterials

关键词：老龄化与健康，分层医学，跨学科，生物工程，骨科植入物免疫反应，化学生物学摘要：该奖学金旨在为转化科学提供独特的跨学科研究机会；该学生将受益于双方合作伙伴（纽卡斯尔和利兹）提供的多种实验方法，同时进行前沿的假设驱动的转化研究，这与MRC当前的交叉主题保持一致，包括分层医学“为每个患者提供最佳治疗”。研究设计是基于当前重要的问题，即关节假体早期失效的潜在原因和后果，这一问题导致大约10%的手术，并需要进行翻修手术，这对医疗保健提供者和患者来说是昂贵的，因为发病率增加。纽卡斯尔大学和利兹大学（指导教授Joanne Tipper）将分别开发一系列细胞、分子和生物工程体外技术，以定义和测量对钴、镍和铬等金属离子化合物以及金属和聚合物磨损颗粒的炎症反应。该学生将在利兹大学（UoL）医学与生物工程研究所的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超高分子量聚乙烯（UHMWPE）以及现代抗氧化剂UHMWPE中生成与临床相关的（尺寸和形态）磨损颗粒。该设备具有独特的能力，通过关节产生无菌的，无内毒素的磨损颗粒，这些颗粒已经通过髋关节模拟器和体内产生的磨损颗粒进行了验证。人们认为，颗粒表面特征在与细胞膜的相互作用中起着至关重要的作用，而在这些类型的研究中经常使用的模型颗粒不会引起细胞与“真实”磨损颗粒相同的反应。粒子将使用在UoL开发的方法进行分离，并使用高分辨率冷场扫描电镜进行表征。该学生将在纽卡斯尔利用巨噬细胞、内皮细胞、成骨细胞和淋巴细胞开发体外模型。这些试验也将用于测试特定的小分子抑制剂和拮抗剂，这些抑制剂和拮抗剂可能会抑制或控制炎症反应。学生还将有机会获得患者的关节液进行分析以及适当的临床数据。此外，电感耦合等离子体质量分光光度法（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。失败的金属种植体周围的种植体周围组织经常被白细胞浸润，这可能导致观察到的免疫效应，包括炎性假瘤形成、软组织坏死和骨溶解。这些因子对白细胞粘附内皮细胞至关重要，这是白细胞向组织迁移所必需的。为了研究作用机制，学生将应用高度复杂的celllix微流体平台来评估细胞在暴露于金属和聚合物生物材料后对单层细胞的粘附和迁移；这个开创性的平台在纽卡斯尔可用模拟微血管流动，而不是更常用的静态培养皿为基础的分析。该学生还将应用基因组技术，使用市售的TLR4 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.