In order to function, all cells in the body require a regular supply of oxygen and continuous removal of waste products. Both are provided by blood delivered through the microvasculature, which comprises vessels smaller than 0.1 mm in diameter. In order to fulfil its function, the flow of blood must be tightly regulated. A key component of this regulation are the specialist 'endothelial cells' that line all microvessels. These cells sense frictional forces arising from the flowing blood and in response release chemical substances that can increase or decrease the size of the vessels to help regulate the flow. When this regulation fails, the results can be devastating. For example, dysregulation of blood flow is one of the first stages in diabetic retinopathy, a condition that threatens the sight of 1% of the world's adult population. It is therefore important to understand the details of how blood flows in microvessels. A major factor that influences microvascular blood flow is the mechanical properties of red blood cells (RBCs). RBCs are highly deformable, which allows them to deform while flowing in larger vessels and even fit through capillaries much smaller than their diameter. RBCs also have a propensity to stick together, in a process called aggregation that is dependent on local flow characteristics. As a result of these RBC behaviours, the flow of blood in microvessels is complex and poorly understood. This is particularly important, because in numerous microvascular diseases, including diabetes, the RBCs become less deformable and aggregate more than in healthy individuals. These changes have been shown to correlate with disease progression, but it has not yet been established exactly how changes to blood properties affect microvascular function. We hypothesise that the changes in RBC properties alter blood flow and hence the frictional forces experienced by the endothelial cells, which in turn leads to dysregulation of flow and ultimately damage to the microvasculature. In this project, we will use state-of-the-art experimental technology to directly evaluate how changes to RBC properties affect microscale blood flow. A key challenge is the complicated branching patterns of the microvessel network. These networks consist of vessels of different sizes, structure and functions, throughout which both RBC flow and concentration change significantly. In order to improve our knowledge of how blood flows in microvessels, we need to be able to measure both the velocity of the RBCs and their local concentration in a given blood vessel or section of a microvascular network. We will achieve this using recently developed optical techniques, combining measurements of light passing through a blood sample with fluorescence measurements of microparticles added to the plasma. Acquiring both of these parameters allows calculation of the frictional forces on the vessel wall, which will be compared to results generated with numerical models. It is not currently possible to make these measurements in humans or living animals, hence we will build realistic models of microvessels using a new technique where laser energy is used to degrade a hydrogel, leaving behind a vessel structure that can be precisely controlled. We will flow blood from healthy volunteers through these models and measure the flow and wall friction under various conditions. We will then chemically treat the blood samples to mimic changes that occur in diabetes and measure the corresponding changes in flow. In addition to providing new insight into blood flow, the evidence generated in this study will reveal how changes to blood mechanical properties might affect diseases such as diabetes. In the long term, this insight is expected to lead to new approaches for diagnosing and treating microvascular diseases.

A vigorous debate has emerged over the primary driver of chemical weathering rates. One hypothesis states that because weathering reactions are driven by pore water chemistry, climate, specifically rainfall, controls chemical weathering rates. In contrast, another hypothesis states that chemical weathering is driven by the supply of 'fresh' minerals to the weathering zone, and the dominant driver of chemical weathering is physical erosion. Studies evaluating the relative importance of these two hypotheses have had limited success. On the one hand, detailed geochemical studies that focus on pore water chemistry make no provision for geomorphic processes such as physical denudation and lateral sediment transport. Such studies cannot yield insights into the mechanisms that drive increased chemical weathering rates from eroding landscapes. This is because chemical weathering rates are spatially heterogeneous (as a century of soil science can attest) and eroding materials continuously move laterally through parts of the landscape with varying chemical weathering rates. On the other hand, studies focusing on weathering rates driven by erosion are largely based on empirical studies of basin wide weathering rates and make no provision for weathering reactions. To truly examine the relative importance of climate and physical erosion on chemical weathering rates, one must account for both weathering reactions and the generation and transport of sediment. In this study the PI proposes, for the first time, to combine a state of the art geochemical model with a detailed geomorphic model. The proposed model will be capable of predicting the coupled geochemical and geomorphic evolution of hillslope soils using both end member chemical weathering hypotheses. To test the model, and the relative importance of the two drivers of chemical weathering, a field site has been identified where the two end member hypothesis predict contrasting spatial distributions of chemical weathering. This field site has a uniquely comprehensive series of both geomorphic and geochemical measurements: at the site measurements exist to independently calibrate the model and compare model results with long term chemical weathering rates and solid state chemistry. Thus, by using a combination of state of the art numerical modelling and an exhaustive geochemical and geomorphic dataset, this project will test if climate (via rainfall and pore water chemistry) or physical erosion rates are dominant in controlling chemical weathering rates in an eroding landscape.

We will launch a new CDT, focused on composite materials and manufacturing, to deliver the next generation of composites research and technology leaders equipped with the skills to make an impact on society. In recent times, composites have been replacing traditional materials, e.g. metals, at an unprecedented rate. Global growth in their use is expected to be rapid (5-10% annually). This growth is being driven by the need to lightweight structures for which 'lighter is better', e.g. aircraft, automotive car bodywork and wind blades; and by the benefits that composites offer to functionalise both materials and structures. The drivers for lightweighting are mainly material cost, fuel efficiency, reducing emissions contributing to climate change, but also for more purely engineering reasons such as improved operational performance and functionality. For example, the UK composites sector has contributed significantly to the Airbus A400M and A350 airframes, which exhibit markedly better performance over their metallic counterparts. Similarly, in the wind energy field, typically, over 90% of a wind turbine blade comprises composites. However, given the trend towards larger rotors, weight and stiffness have become limiting factors, necessitating a greater use of carbon fibre. Advanced composites, and the possibility that they offer to add extra functionality such as shape adaptation, are enablers for lighter, smarter blades, and cheaper more abundant energy. In the automotive sector, given the push for greener cars, the need for high speed, production line-scale, manufacturing approaches will necessitate more understanding of how different materials perform. Given these developments, the UK has invested heavily in supporting the science and technology of composite materials, for instance, through the establishment of the National Composites Centre at the University of Bristol. Further investments are now required to support the skills element of the UK provision towards the composites industry and the challenges it presents. Currently, there is a recognised skills shortage in the UK's technical workforce for composites; the shortage being particularly acute for doctoral skills (30-150/year are needed). New developments within industry, such as robotic manufacture, additive manufacture, sustainability and recycling, and digital manufacturing require training that encompasses engineering as well as the physical sciences. Our CDT will supply a highly skilled workforce and technical leadership to support the industry; specifically, the leadership to bring forth new radical thinking and the innovative mind-set required to future-proof the UK's global competitiveness. The development of future composites, competing with the present resins, fibres and functional properties, as well as alternative materials, will require doctoral students to acquire underpinning knowledge of advanced materials science and engineering, and practical experience of the ensuing composites and structures. These highly skilled doctoral students will not only need to understand technical subjects but should also be able to place acquired knowledge within the context of the modern world. Our CDT will deliver this training, providing core engineering competencies, including the experimental and theoretical elements of composites engineering and science. Core engineering modules will seek to develop the students' understanding of the performance of composite materials, and how that performance might be improved. Alongside core materials, manufacturing and computational analysis training, the CDT will deliver a transferable skills training programme, e.g. communication, leadership, and translational research skills. Collaborating with industrial partners (e.g. Rolls Royce) and world-leading international expertise (e.g. University of Limerick), we will produce an exciting integrated programme enabling our students to become future leaders.

We propose to create a world-leading programme to search for spatial and temporal variations of fundamental constants of nature, using a network of quantum clocks. Our consortium will build a community that will achieve unprecedented sensitivity in testing variations of the fine structure constant, alpha, and the proton-to-electron mass ratio, mu. This in turn will provide more stringent constraints on a wide range of fundamental and phenomenological theories beyond the Standard Model and on dark matter models. The ambition of the QSNET consortium will be enabled by a unique experimental platform that connects a number of complementary quantum sensors across the UK, namely state-of-the-art atomic clocks, molecular clocks, and a highly-charged ion clock. Key to the proposal is the networked approach in which clocks, with different sensitivities to changes of the fundamental constants, will be linked using optical fibres. The network involves a range of different quantum sensing devices and devices with different technology readiness levels: from the more established microwave atomic clocks on the one end to the highly-charged ion clock on the other. QSNET will be able to deliver important results in the first years, and at the same time develop advanced quantum sensors to provide increasingly impactful results as the project continues and the most sophisticated sensors come on line.

3D Printing elicits tremendous excitement from a broad variety of industry - it offers flexible, personalised and on demand scalable manufacture, affording the opportunity to create new products with geometrical / compositional freedoms and advanced functions that are not possible with traditional manufacturing practices. 3D Printing progresses rapidly: for polymerics, we have seen significant advances in our ability to be able to manufacture highly functional structures with high resolution projection through developments in projection micro stereolithography, multimaterial ink jet printing and two photon polymerisation. There have also been exciting advances in volumetric 3DP with the emergence of Computational Axial Lithography and more recent work such as 'xolo'. Alongside these advances there has also been developments in materials, e.g., in the emergence of '4D printing' using responsive polymers and machine learning / AI on 3DP is beginning to be incorporated into our understanding. The impact of these advances is significant, but 3D printing technology is reaching a tipping point where the multiple streams of effort (materials, design, process, product) must be brought together to overcome the barriers that prevent mass take up by industry, i.e., materials produced can often have poor performance and it is challenging to match them to specific processes, with few options available to change this. Industry in general have not found it easy to adopt this promising technology or exploit advanced functionality of materials or design, and this is particularly true in the biotech industries who we target in this programme grant - there is the will and the aspiration to adopt 3D printing but the challenges in going from concept to realisation are currently too steep. A key challenge stymying the adoption of 3D printing is the ability to go from product idea to product realisation: each step of the workflow (e.g., materials, design, process, product) has significant inter-dependent challenges that means only an integrated approach can ultimately be successful. Industry tells us that they need to go significantly beyond current understanding and that manufacturing products embedded with advanced functionality needs the capability to quickly, predictably, and reliably 'dial up' performance, to meet sector specific needs and specific advanced functionalities. In essence, we need to take a bottom-up, scientific approach to integrate materials, design and process to enable us to produce advanced functional products. It is therefore critical we overcome the challenges associated with identifying, selecting, and processing materials with 3DP in order to facilitate wider adoption of this pivotal manufacturing approach, particularly within the key UK sectors of the economy: regenerative medicine, pharmaceutical and biocatalysis. Our project will consider four Research Challenges (RCs): PRODUCT: How can we exploit 3D printing and advanced polymers to create smart 21st Century products ready for use across multiple sectors? MATERIALS: How can we create the materials that can enable control over advanced functionality / release, that are 3D Printable? DESIGN: How can we use computational / algorithmic approaches to support materials identification / product design? PROCESS: How can we integrate synthesis, screening and manufacturing processes to shorten the development and translation pipeline so that we can 'dial up' materials / properties? By integrating these challenges, and taking a holistic, overarching view on how to realise advanced, highly functional bespoke 3D printed products that have the potential to transform UK high value biotechnology fields and beyond.