The research, which will be carried out in the School of Engineering at the University of Glasgow, will underpin a completely new paradigm in the handling of liquids. It involves the control of the mechanical interactions between fluids and microfabricated structures, with acoustic waves. Notwithstanding its potential impact on a wide range of areas (e.g. physics and chemistry), my focus in this Fellowship will be in enabling advanced diagnostics both in remote areas in developing countries and in the developed world, by integrating complex biological sample processing on low cost portable devices. Acoustic waves carry a mechanical energy that has been successfully used to actuate a wide range of liquid functions. In particular, Surface Acoustic Waves (SAW) propagated on piezoelectric surfaces, using transducers commonly found in electronics, can refract in a liquid, leading to recirculation flows. I have pioneered and enhanced a technique to control SAW and their interactions with the liquid and particles, enabling more complex manipulations. The new platform is based on micromanufactured, disposable phononic lattices, that scatter or reflect the acoustic waves in a frequency dependent manner. These structures shape the acoustic waves, in a manner analogous to that of holograms shaping light. The structures rely on mechanical contrast when holograms are based on refractive index. Geometric aspects of the hologram's design provide colours of different frequencies; here, the phononic lattice geometry determines the frequency at which the sound is scattered. The different frequencies of ultrasound interact with different phononic structures to give different functions, providing a "tool-box" of different diagnostic processes (sample processing, cell separation, detection), which, when combined, form a fluidic circuit, a complete diagnostic assay. Contrary to the established microfluidic systems used in point-of-care devices, which rely on flow through channels to carry out different functions at different positions within the channels, I will design, fabricate, characterise and use new phononic lattices to combine different functions in the frequency domain, on a stationary sample. Others involved in the research include Professor Miles Padgett (School of Physics), Professor Andy Waters (Welcome Centre for Molecular Parasitology), Dr Andrew Winters (Consultant in Sexual Health & HIV Medicine and Joint Clinical Director at The Sandyford Clinic, NHS Greater Glasgow and Clyde) and Dr Mhairi Copland (Paul O'Gorman Leukaemia Research Centre and the Beatson Cancer Research. My research will have three potential outcomes in diagnostics and sensing, namely the development of new Microsystems technologies for: 1. Drug resistant malaria diagnostics. I will develop phononic geometries to carry out a complete nucleic acid based test, including sample preparation, amplification, and detection in whole blood. These will be fabricated in low cost materials (e.g. glass, composites) and could transform malaria diagnostics in the Developing World. 2. Multiplexed detection of a panel of sexually transmitted diseases, working with the NHS. The ability to perform complex sample preparation has the potential to integrate multiplexed analysis in an expert system, where instead of a diagnostic test centered around a pathogen, the test has the capability to analyse a set of symptoms, a decisive shift in diagnostics. 3. Stratification of leukemia cells' aggressiveness. I will explore how the combination of the cells mechanical information probed using acoustics, and coupled with electrical information on cell membranes, could enable a multidimensional analysis of cells. This research will have the potential to create devices to carry out diagnostics anywhere.

Osteoarthritis affects over eight million people in the UK alone, with nearly three quarters of patients reporting some form of constant pain. Treatment for arthritis is estimated to cost the UK healthcare system over £10 billion per year, with significant additional societal costs for lost working hours and welfare payments. Although hip and knee replacement surgeries are considered successful, these treatments are not suitable for all patients and some devices fail early, requiring costly and less successful revision surgery. There are over 15,000 revision surgeries performed in the UK alone each year. Younger and more active patients, as well as rising numbers with obesity, are placing greater demands on these treatments: implants need to last for longer and withstand more extreme loading than ever before. There is evidence that both individual patient biomechanics and surgical choices influence the outcomes of these treatments. Improved outcomes, particularly for more challenging patient groups, can only be achieved by better matching the treatment to the functional requirements of the individual patient. This proposal will bring together complementary research expertise from two of the world's leading research institutes in the field to build the evidence needed to enable treatments for osteoarthritis to be better tailored to individual patient needs. The Institute of Medical and Biological Engineering at the University of Leeds has developed unique capability and expertise to evaluate artificial and natural joints. These include the world's largest academic facility for experimentally testing joint replacements, as well as computational modelling methods to simulate how implants perform in the body. These capabilities enable the mechanical performance of implants to be evaluated under a range of different conditions, for example to study how the implant wears over time or becomes damaged with usage. The Center for Orthopaedic Biomechanics at the University of Denver has developed world-leading capability in measuring patient joint mechanics in vivo, including methods of imaging patient joints as they undertake different activities, and parallel computational methods for deriving biomechanical information. These methods enable the forces and motions on an individual patient's hip or knee joints to be derived and, by collecting data on many patients, examine how these differ from one individual to another. By combining the expertise across both groups, this Centre-to-Centre Research Collaboration will enable relationships to be developed between an individual patient's characteristics (e.g. their anatomy and how they load their joints) and the mechanical performance of the implant. Specifically, in the hip we will combine methodologies developed at the two centres to evaluate how patient and surgical factors affect the risk of early failure in hip replacements due to the device components pushing into each other or the surrounding bone (impingement), or the way the components are aligned. We will also examine how different choices of implant can influence the outcomes. In the knee, we will combine methodologies to identify how patient factors (such as the anatomy of the knee and the way it is loaded during different activities) affect early-stage treatments for knee osteoarthritis. We will also examine the effects of a greater range of activities, such as squatting and stair climbing, on the outcomes of knee replacements. These studies will bring together different methodologies and build new pathways for acquiring and sharing data that can be adopted more widely and applied to other musculoskeletal systems in the future. The work will build the evidence needed to improve hip and knee implant design, inform clinical decision-making, enhance patient quality of life and reduce early complications.

Definition: A rapidly developing area at the interfaces of engineering/physical sciences, life sciences and medicine. Includes:- cell therapies (including stem cells), three dimensional cell/ matrix constructs, bioactive scaffolds, regenerative devices, in vitro tissue models for drug discovery and pre-clinical research.Social and economic needs include:Increased longevity of the ageing population with expectations of an active lifestyle and government requirements for a longer working life.Need to reduce healthcare costs, shorten hospital stays and achieve more rapid rehabilitationAn emergent disruptive industrial sector at the interface between pharmaceutical and medical devicesRequirement for relevant laboratory biological systems for screening and selection of drugs at theearly development stage, coupled with Reduction, Refinement, Replacement of in vivo testing. Translational barriers and industry needs: The tissue engineering/ regenerative medicine industry needs an increase in the number of trained multidisciplinary personnel to translate basic research, deliver new product developments, enhance manufacturing and processing capacity, to develop preclinical test methodologies and to develop standards and work within a dynamic regulatory environment. Evidence from N8 industry workshop on regenerative medicine.Academic needs: A rapidly emerging internationally competitive interdisciplinary area requiring new blood ---------------------

Viral infections pose one of the biggest global threats to human populations and agriculture. Successful prevention, monitoring and treatment of viral infections requires the availability of fast and reliable diagnostic methods which can not only sensitively, but rapidly detect a viral infection of interest and differentiate between viral infections. This is particularly important in the winter months where rapid diagnosis of viral infections emerging from SARS-Cov-2 relative to influenza strains is essential in order to assist medical practitioners to suggest the most appropriate interventions and treatment. At present, methods do not exist which can rapidly detect viral infections in a low-cost, point-of-care device. We propose to develop a biosensing technology which can not only detect viral components, but also has the potential for the platform to be reusable and regeneratable. Central to these developments is the use of fluorous technology as a tool to immobilise elements which detect viral components. Much akin to Teflon, fluorous technology has the dual advantage as a method which can immobilise molecular components which have a complementary fluorous tag, and reduces non-specific binding to non-fluorous biomolecules, thus improving the sensitivity of the approach. Furthermore, the fluorous-directed immobilisation event is inherently reversible by a simple washing step with organic solvent. In this proposal, we will demonstrate the modularity of the strategy to detect viral RNA (by RT-PCR) or protein (by direct detection of intact viral particles). This will provide a powerful new tool for the biosciences which has the potential to be used for any application which requires rapid detection of pathogenic infections.

In the past decade, over 2.5 million people in the UK had a metal device implanted to replace a skeletal joint in their body. With our chances of living to 100 years old predicted to double in the next 50 years, these bone implants will need to last substantially longer. Alarmingly, current data demonstrates that failure rates rapidly increase each subsequent year after implantation. The metals we currently make bone implants from were not specifically developed for use within the body. Instead, these materials were originally designed for aerospace applications. In addition to being much stiffer than bone, these metal alloys may also contain toxic elements that cause adverse biological reactions. The aim of this fellowship is to design a new generation of bioinspired alloys that promote advantageous cellular responses while exhibiting mechanical properties that are aligned with the body. In order to design the ideal biomedical alloy, there are a number of properties that need to be balanced, for example biocompatibility (i.e. non-toxic), mechanical performance, and wear resistance. Optimising lots of parameters simultaneously via current trial-and-error approaches may take years or even decades. To significantly speed up this process, a computational modelling approach, called Alloys-By-Design (ABD), will be used to discover a range of titanium compositions that match the mechanical properties of bone. For the first time, by searching for alloys with specific microstructures, ABD will be employed to identify compositions with promising biological functionality, such as infection prevention. Since ABD is a theory-based approach, it will be important to validate the model predictions. This will be done by using a unique laser-based system to melt together all the alloying elements. To maintain rapid progress towards using these new metals clinically, a novel high throughput test will be developed as a screening tool to identify compositions that provoke promising mammalian and bacterial cell responses. From these results, non-toxic and antimicrobial compositions will be selected. High resolution microscopy will subsequently be used to understand the relationships between alloying elements, microstructure and biological behaviour. Before bone implants made of these new alloys may be implanted into patients, it will be critical to deepen our understanding of how the body may respond. Importantly, the behaviour of various cell types involved in bone regeneration will be considered, including bone forming osteoblasts and stem cells found in bone marrow. The rate at which these cells grow and their ability to form new bone on the surface of the novel alloys will be benchmarked against currently used metals. Since it is known that ions may leach from alloys within the body and cause damage to surrounding tissue, this will also be carefully studied. The patient and economic benefits gained from personalised devices that anatomically fit perfectly is rapidly growing in bone implants. As such, the possibility to 3D print bespoke implants made from the most promising bioinspired alloy will be explored. For the first time, the ability to locally tailor alloy composition in-situ using a metal laser-based 3D printer will be investigated. By systematically changing the laser processing parameters and characterising the resultant composition, a universal protocol to optimise in-situ alloy formation will be developed. This will open up an entirely new dimension of bone implant customisation, making it possible to tailor mechanical performance or biological functionality in selected areas of a single implant. Underpinning this fellowship is an experienced clinical and industrial advisory board that will support translation of these novel bioinspired alloys. This will ensure that the research may be transformed into approved medical devices that improve patient lives, reduce healthcare costs, and grow the UK economy.