As quality of life constantly improves, the average lifespan will continue to increase. Underlining this improvement is the vast amount of the UK government's support to NHS (£133.5 billion in year 2011/12) and the UK pharmaceutical industry's R&D large investment (4.9 billion to R&D in year 2011/12). The expectation of quality healthcare is inevitably high from all stakeholders. Fortunately recent advances in science and technology have enabled us to work towards personalised medicine and preventative care. This approach calls for a collective effort of researchers from a vast spectrum of specialised subjects. Advances in science and engineering is often accompanied by major development of mathematical sciences, as the latter underpin all other sciences. The UoL Centre will consist of a large and multidisciplinary team of applied and pure mathematicians, and statisticians together with healthcare researchers, clinicians and industrialists, collaborating with 15 HEIs and 40 NHS trusts plus other industrial partners and including our strongest groups: MRC Centre in Drug Safety Science, Centre for Cell imaging (CCI for live 3D and 4D imaging), Centre for Mathematical Imaging Techniques (unique in UK), Liverpool Biomedical EM unit, MRC Regenerative Medicine Hub, NIHR Health Protection Research Units, MRC Hub for Trials Methodology Research. Several research themes are highlighted below: Firstly, an improved understanding of the interaction dynamics of cells and tissues is crucial to developing effective future cures for cancer. Much of the current work is in 2D, with restrictive assumptions and without access to real data for modelling. We shall use the unparalleled real data of cell interactions in a 3D setting, generated at UoL's CCI. The real-life images obtained will have low contrast and noise and they will be analysed and enhanced by our imaging team through developing accurate and high resolution imaging models. The main imaging tools needed are segmentation methods (identifying objects such as cells and tissues regions in terms of sizes, shapes and precise boundaries). We shall propose and study a class of new 3D models, using our imaging data and analysis tools, to investigate and predict the spatial-temporal dynamics. Secondly, better models of how drugs are delivered to cells in tissues will improve personalised predictions of drug toxicity. We shall combine novel-imaging data of drug penetration into 3D experimental model systems with multi-scale mathematical models which scale-up from the level of cells to these model systems, with the ultimate aim of making better in-vitro to in-vivo predictions. Thirdly, there exist many competing models and software for imaging processing. However, for real images that have noise and are of low contrast, few methods are robust and accurate. To improve the modelling, applied and pure mathematicians team up to consider using more sophisticated tools of hyperbolic geometry and Riemann surfaces and fractional calculus to meet the demand for accuracy, and, applied mathematicians and statisticians will team up to design better data fidelity terms to model image discrepancies. Fourthly, resistance to current antibiotics means that previously treatable diseases are becoming deadly again. To understand and mitigate this, a better understanding is needed for how this resistance builds up across the human interaction networks and how it depends on antibiotic prescribing practices. To understand these scenarios, the mathematics competition in heterogeneous environments needs to be better understood. Our team links mathematical experts in analysing dynamical systems with experts in antimicrobial resistance and GPs to determine strategies that will mitigate or slow the development of anti-microbial resistance. Our research themes are aligned with, and will add value to, existing and current UoL and Research Council strategic investments, activities and future plans.

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.

Many existing challenges, from personalized health care to energy production and storage, require the design and manufacture of new molecules. However, identifying new molecules with desired properties is difficult and time-consuming. We aim at accelerating this process by exploiting advances in data availability, computing power, and AI. We will create generative models of molecules that operate by placing atoms in 3D space. These are more realistic and can produce better predictions than alternative approaches based on molecular graphs. Our models will guarantee that the generated molecules are synthetically accessible upfront. This will be achieved by mirroring realistic real-world processes for molecule generation where reactants are first selected, and then combined into more complex molecules via chemical reactions. Additionally, our methods will be reliable, by accounting for uncertainty in parameter estimation, and data-efficient, by jointly learning from different data sources. Our contributions will have a broad impact on materials science, leading to more effective flow batteries, solar cell components, and organic light-emitting diodes. We will also contribute to accelerate the drug discovery process, leading to more economic and effective drugs that can significantly improve the health and lifestyle of millions.

Vaccines are the most successful public health initiative of the 20th century. They save millions of lives annually, add billions to the global economy and extended life expectancy by an average of 30 years. Even so, the UN estimates that globally 6 million children each year die before their 5th birthday. While vaccines do exist to prevent these deaths, it is limitations in manufacturing capacity, technology, costs and logistics that prevent us for reaching the most vulnerable. The UK is a world leader in vaccine research and has played a significant leadership role in several public health emergencies, most notably the Swine Flu pandemic in 2009 and the recent Ebola outbreak in West Africa. While major investment has been made into early vaccine discovery - this has not been matched in the manufacturing sciences or capacity. Consequently, leading UK scientists are forced to turn overseas to commercialise their products. Therefore, this investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. We will create a vaccine manufacturing hub that brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry and policy makers together to propose radical change in vaccine development and manufacturing technologies, such that the outputs are suitable for Low and Middle Income Countries. The vaccine manufacturing challenges faced by the industry are to (i) decrease time to market, (ii) guarantee long lasting supply - especially of older, legacy vaccine, (iii) reduce the risk of failure in moving between different vaccine types, scales of manufacture and locations, (iv) mitigating costs and (v) responding to threats and future epidemics or pandemics. This work is further complicated as there is no generic vaccine type or manufacturing approach suitable for all diseases and scenarios. Therefore this manufacturing Hub will research generic tools and technologies that are widely applicable to a range of existing and future vaccines. The work will focus on two main research themes (A) Tools and Technologies to de-risk scale-up and enable rapid response, and (B) Economic and Operational Tools for uninterrupted, low cost supply of vaccines. The first research theme seeks to create devices that can predict if a vaccine can be scaled-up for commercial manufacture before committing resources for development. It will include funds to study highly efficient purification systems, to drive costs down and use genetic tools to increase vaccine titres. Work in novel thermo-stable formulations will minimise vaccine wastage and ensure that vaccines survive the distribution chain. The second research theme will aim to demystify the economics of vaccine development and distribution and allow the identification of critical cost bottlenecks to drive research priorities. It will also assess the impact of the advances made in the first research theme to ensure that the final cost of the vaccine is suitable for the developing world. The Hub will be a boon for the UK, as this research into generic tools and technologies will be applicable for medical products intended for the UK and ensure that prices remain accessible for the NHS. It will establish the UK as the international centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the most vulnerable, especially children.

Lung diseases are a major global health burden. 300 million people live with asthma worldwide and it is predicted that chronic obstructive pulmonary disease will become the third-leading cause of death by 2020. The inhalation of therapeutic aerosols is a familiar medical strategy to treat lung diseases. Aerosol therapy can also achieve high antibiotic concentrations in the lung to treat infections. When aerosols are targeted into the deep lung, inhaled therapy also provides a means to achieve systemic concentrations of active pharmaceutical ingredients and avoid the need for injections of drugs that are destroyed in the gastrointestinal tract, such as insulin. Despite its potential, many patients fail to gain the full benefits of inhaled therapies in treating lung disease, and systemic drug delivery has failed to achieve the market break-through it deserves. Some of the ineffectiveness arises from the inability of patients to use their therapy correctly. However, achieving aerosol deposition in the lungs is a major challenge even for those patients with good inhaler technique. The challenge is to produce a portable dosage form containing components that can be redispersed by a patient. Redispersion must be achieved with uniformity of a dose in the form of an aerosol with the properties required for lung penetration. Turning potentially inhalable particles into formulated products that can be manufactured reproducibly, and that achieve consistent aerosolization performance between different patients poses many challenges that are poorly-solved. Consensus meetings of industrial, academic and regulatory experts in the field of inhaled medicine have identified the need to improve control and consistency of drug deposition performance. Additionally there is a need to improve our understanding of how and why the characteristics of starting materials interact with the manufacturing conditions to lead to inter-batch and inter-patient variability in aerosol characteristics. At the heart of the challenge is the fact that the very property of the particles that makes them suitable for inhalation (their small size which, at less than 5 microns, is less than the diameter of a human hair) also causes them to clump together as agglomerates. Theme 1 of the project will employ synthonic engineering (a computer modelling technique based on the molecular structures of pharmaceutical ingredients) to achieve new abilities to predict agglomeration behaviour early in development, and the interactions of agglomerate materials with inactive ingredients in the formulation. Theme 2 will use new measurement techniques that image how agglomerates interact with each other in powders to develop an understanding and characterize how the agglomerate phase in a formulation leads to inter-patient or inter-batch variability of product performance. Theme 3 will underpin the knowledge gained from powder imaging to assess the underlying causes of agglomeration. Better, integrated experimental measurement techniques will be developed to characterize the material properties that regulate the extent and strength of interactions between particles. Theme 4 focuses on developing new computational models to characterize the behaviour of agglomerated powders during the mechanical processes occurring when a patient breathes through an inhaler, and when powders are processed during manufacturing. The final component of the project is to integrate the knowledge gained in Themes 1-4 to engineer quality into a range of test products selected by an advisory panel. This will be achieved by using the prediction and measurement techniques to inform formulation scientists, device designers and process engineers of the steps that are appropriate to mitigate the effects of agglomeration on product performance. The ultimate goal is to use the techniques developed to translate the therapeutic benefits for patients using inhaled medicines from molecules to manufactured products.