Bioengineering in Action : Stratifying the immune reponse to biomaterials

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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.